Flashcards

Pharmacology

ghaznia.khan English 103 cards

Cards in this deck (103)

1What is the definition of pharmokinetics and what are the 5 stages. Define each.Pharmacokinetics is what your body does to the drug: how your body absorbs it, distributes and metabolizes the drug. 5 stages are Administration, Absorption, Distribution, Metabolism and Elimination. Absorption - transport of drug into plasma
Distribution - to all the organs
2What is the definition of administration?Adjust drug delivery to optimize drug
availability at the therapeutic target. It doesn't matter how much drug is given, but how we give that drug to reach the maximum effective therapeutic concentration where we want it to work.
3what are the different routes of administration?Topical (delivered to site where you want it to work) vs. Systemic (distributed to entire system and eventually meets target). Both associated with syringe
Enteral (through enteric systemic usually orally) vs. Parenteral (adjacent or around enteric system, through surface or syringe)
4What are the three ways drugs can be given through the enteric system. Describe absorption rate, first pass effect, and indications.
5Why does oral administration have max first pass effect?Swallow drug --> stomach (absorption) --> portal vein --> liver (most of it is broken down before going to target) --> hepatic v --> RA --> RV --> pulmonary circ --> LA --> LV --> aorta --> systemic --> target
6Why does sublingual administration have NO FIRST PASS EFFECT?BY-PASS LIVER - no loss of drug
Mouth --> sublingual mucosa (thin and vascularized, fast absorption) --> RA --> RV --> pulmonary circ --> LA --> LV --> systemic --> target. Immediately after absorption, the drug from the oral cavity, goes into the right atrium and by passes the liver. Administration of a drug through the buccal cavity is going to by pass the FIRST PASS EFFECT and there is no loss of the drug. This is limited to a small number of drugs. Drugs that have a bad taste cannot be administered this way.
7Does rectal administration pass or not pass the first pass effect??DEPENDS WHERE IT IS ABSORBED WITHIN RECTUM. Terminal part will by-pass portal v (no first pass). Intermediate portion: mixed venous return, some by-pass, some goes to portal v, Upper third: input from v that go to liver, first pass effect.
Upper/Middle Rectum > portal v > liver > heart > systemic > target
8Describe all the ways that parenteral drug delivery can happen
9Is using a syringe mean that the delivery will be systemic?NO:
Although we normally associate the use of syringes for systemic administration of the drug (because we always think of intravenous, intramuscular administration of the drug), there are situations where the usage of a syringe in performing an injection, does not mean that the drug will be systemically administered.
e.g topical anesthetic
10What are the advantages and disadvantages to parenteral delivery?
11Rank intranasal, parenteral, inhalation and oral drug administration from rapid to slow action rate.1) Parenteral --> directly into blood stream
2) Intra-nasal --> mucosa is very absorptive
3) Inhalation --> drug goes directly into lungs and heart and bypasses first pass effect
4) oral --> much slower
12Describe difference between single vs. repeated and intermittent vs. continuous and give an example of each.Single - local anesthetic
Repeated - not given once, anti-biotics
Intermittent - every 4-6 hours
Continuous - drips/IV etc.
13Describe the different stages. What type of administration?Single Oral:
Time 0: delay until the maximum concentration of drug reaches the blood and then reaches the target.
Time 0-1: absorption in GI tract, slow increase of conc. in plasma
Peak: absorption, effect of deployment. distribution, to all organs.
Time 2-3: liver metabolizes, kidney eliminates
14What type of admin is this? Describe. Is this an effective way to administer drug?IV Injection: max concentration as soon as its given, distribution and elimination cause concentration to decline and concentration goes to 0 when there is no more in body. Then inject again.
Effective way to administer as long as you give every few hrs (eg. anti-biotic)
15What type of administration is this? Describe. What does the plateau represent?Multiple dosing of IV at the same dosage. Inject every 3 hrs for e.g, slowly start building up drug concentration.
Plateau: Concentration Steady State - The right dosage in the body where there is a perfect balance between the amount of drug that goes in plasma and the amount of drug that gets eliminated.
16What type of admin is this? Describe. Is this an injection?Cont IV infusion - give drug constantly in minute amounts until it reaches CSS (plateau). End of infusion is when metabolism/elimination overtakes admin and conc decreases.
NO - continuous infusion.
17Define drug absorptionTransfer of drug from site of administration into the bloodstream
18What are the factors influencing drug absorption?1. Tissue Barriers to Drug Movement
2. Mechanisms of Drug Absorption
3. Molecular Size of Drug
4. Drug Protonation
(charged vs. uncharged)
5. Drug solubility
(Poil/water = oil/water partition coefficient)
6. Drug Binding to Proteins
19What are tissue barriers to drug absorption?1) Cell membranes + tight junctions - epithelial barriers.
2) Capillary Permeability Unrestricted Mov- fairly easy to get into blood stream. systemic capillaries have gaps (b/w endo cells can open and close to allow big things to go through) and fenestras (holes that allow direct contact b/w blood vessel and cell). Drug can go into these
windows as long as they are 25K daltons (pinocytosis)
3) Renal capillaries - fenestras can allow 70K MW to go through. Albumin barely fits here, so if it is in urine, then system is leaky.
4) Brain Capillaries - No tight junctions or fenestras so only way for drug to get in is through energy transport (ion pumps, diffusion)
20What are the two ways drugs cross cell membranes?1) Passive Diffusion - water/lipid soluble drugs
2) Active Transport -pino/endo/phagocytosis or gap junctions
21Describe water vs. lipid soluble drugs and how they cross membrane. what is common between the two?water soluble - happens through a transmembrane protein channel.
lipid soluble - lipid molecules accumulate and PUSH through membrane eventually. aquaporins are the channels (MW < 150-200 Da)
BOTH OCCUR DOWN CONCENTRATION GRADIENT
22What does this graph show?Cut Off phenomenon - passive diffusion in oil and aqueous media in GI system.
enterocytes have double layer of phospholipid and transmembrane proteins and glycoproteins and sugars which attract thin layer on top of thin layer of phoshpholipids. substance cannot be too lipid soluble, bc it can't cross that outer layer of water.
6. Looking at the graph
- The increase in lipid solubility in the intestine:
- It won't get absorbed if it is very lipid soluble because of the water layer. You have to balance lipid/water solubility to cross.
23What is the last mechanism of drug absorption?carriers - energy dependant or independant.
24Describe diff between pinocytosis/phagocytosis, endocytosis or receptor mediated endoPino/Phago - large molecules engulfed if they are water soluble.
Endo - larger molecules
Receptor Mediated - receptors target certain mocs to come into the cell.
25What is another way that passive diffusion of water drugs can happen through?Gap Junctions - adjacent aquaporins, allows communication between cells.
26Describe how drug protonation/ionization affects absorptionneutral (non-ionized) substances cross membrane well.
Acidic Substances - need to be protonated in stomach for them to be neutral and absorbed.
Basic Substances - - If you ingest it orally, it will become protonated and will be charged. It won't be able to cross membranes.
- If you think of morphine and someone ingesting morphine as a pain killer, it is usually admin by intrave
27Is the pH the only factor in drug protonation?No, the surface area of the organ is also important and efficiency at absorption is also important. for e.g. small intestines have a larger surface area and therefore absorb MORE ethanol MORE efficiently than stomach. Morphine is NOT absorbed in stomach, only in SI.
28—This phenomenon is called ion trapping. Acidic drugs (aspirin) - ion charged, can get trapped in the urine bc it is water soluble.
basic drugs (morphine) - eliminated only in small amounts in the urine bc it is not water soluble.
29—High Poil/water - accumulates in membrane given lipid solubility, will continue to work even hours after admin bc it will be released from the membrane as levels in plasma go down.
Low Poil/water - accumulates on either side of the membrane.
30What are the factors that affect binding to plasma proteins
31Describe the nothing principle
32True or False: the percentage of drug that is bound to protein is always the same regardless of the amount of drug present in the body.TRUE: If I have 1 ton of drug, 90% is bound to protein. This means that 90% of a ton is bound to protein.
- If I have 1 gram, 90% of 1 gram is bound to protein.
33What happens if Drug A and Drug B bind to the same protein?- The only way for Drug B to bind to protein is to displace some of Drug A that was originally binding to protein.
- If you have competition, the second drug is going to displace some of the previous one. So what? Just look at it this point of view:
- If I have a drug that is bound by 90% and only 10% is free, if I have a Second Drug that is going to release another 10-20% of what was bound, I am going to double or triple the concentration of Drug A without changing the dose of what I gave to the patient. This occurs in the relationship between blood, drugs and protein.
- By doing this, you doubled or tripled the dose of the drug without really giving more of it. This process is dynamic and reversible.
The affinity of the binding is very weak - it is easy to bind and easy to uncouple / displace / compete against.
34Describe intra and extracellular distribution of water
35Describe water accessibility in the body. What % of body comp is water. How much is extra cell vs. intra cell. How much is intravascular vs. interstitial.
36—
37A tissue that is well vascularized will recieve drug ____ and a tissue that is poorly vascularized (e.g fat) will recieve drug _____. A tissue that is well vascularized will eliminate drug ____ and a tissue that is poorly vascularized will eliminate drug ______ and store it _______faster, slower, faster, slower, longer
38Define clearance, biotransformation and excretion. What is clearance a product of? What organs come to mind when thinking of bio transformation and excretion?clearance = biotransformation + elimination.
Bio trans = liver
Excretion = kidney
39What is total body clearanceCl total = Clhepatic + Clrenal + CLother
40describe the difference between polar drug elimination and non-polar drug elimination.Polar = water soluble = directly through kidney/urine
Non-polar = hepatic bio transformation:
1) Transformed into polar metabolite for excretion through kidney
2) Non-polar metabolite by bile through liver, broken down slowly.
41The interaction between enzyme and drug can result in what three actions?Activation: Inactive drug converted to Active metabolite. e.g. dopamine cannot cross BBB, so L-dopa is given to form more dopamine in brain.
Maintenance of Activity: Active Drug --> Active metabolite metabolized into Active Metabolite. e.g. morphine is a pain killer, but one of its metabolite is also a PK.
Inactivation: Active Drug --> Inactive Metabolite (no relevant bioactivity)
42What are the characteristics for phase I rxns. Where do these rxns occur for the most part (liver).
43T/F: 80% of phase I rxns occur by CYP enzymes? Which enzyme is responsible for the majority of these rxns? What drugs are metabolized by this enzymeTrue
CYP3A4 metabolizes approx. 50% of phase I rxns.
Acetominophen and lidocane (local anesthetic)
44What happens when you stimulate CYP3A4 and when you inhibit it. for e.g. in the case of acetominophen. Why is this important?Stimulate CYP3A4: increase metabolism of its substrate. Body will eliminate drug faster.
Inhibit CYP3A4: fluconozole inhibits CYP3A4 50%. It takes CYP3A4 2X longer to metabolize and eliminate drug from body.
This is why its important to ask about drug-drug interactions or even drug interactions with natural products. For e.g. graprefruit is a CYP3A4 inhibitor as well.
45Describe phase II rxns.
46Describe how glucathione conjugate worksglucaronide produced byl liver cells, binds to drug via UDP-glucuronyl transferance which is now inactive and can be eliminated
47What are the major effects once enzyme drug interacts?Cont Enzymatic Expression
Induction
Inhibition
48—Black Line - control. placebo, so no metabolism of drug.
Pink Line - carcinogen, starts to get metabolized and goes down once elimination begins.
Red line - 4uL of dose, metabolism faster, metabolites are also carcinogenic so buildup of carcinogens.
Indunction at different levels can have diff outcomes.
49What is the difference between phase I and phase II rxns
50T or F? Acetominophen can be metabolized by phase I and phase II rxns.T
Normal: metabolized by phase II (95%), 5% will be metabolized by CYP 2E1 which converts it into toxic NAPQI. Phase II than conjudates NAPQI and gluthathione which is then mopped up.
Liver problems: there isn't enough gluthathione for mopping up, NAPQI builds up and becomes toxic. TWO phase II rxns blocked, further compounding toxicity of original compound by 3-5x.
51What other factors affect bio transformation?
52What are the age dependant factors on metabolism of drugs and how do they vary with age.Water content - less body water as we get older
Lipophillic drug in fatty tissue - More fat as we get older
Liver metabolism of drug - peaks at young adults (20s). Low in infant and elderly.
Kidney elimination - peaks at young adults (20s). Low in infant and elderly. Lower in neonates
53what are the 3 components of renal excretion?1) GFR = 120ml/min. filtrate/min. Creatine is water soluble, so found in urine.
2) Tubular Secretion: pumping of additional mocs in filtrate, concentration of something in urine greater than plasma. We can take advantage of this with ABs for urinary bladder than are secreted into filtrate.
3) Tubular Resorption - pumping from filtrate into blood. diabetic patients have high glucose in their urine so it leaks back into plasma. good indicator of how well diabetic medications are working.
54What phenomenon is this?Neutral drugs cross membranes. Charged drugs don't. Sodium bicarbonate increases the excretion of weak acidic drugs. Raise the pH of urine a lot, so that weak acid loses the proton and cannot re-enter the body (ion trapping).
55What phenomenon is this?Ion trapping for weak bases with ammonium chloride. Enhance excretion of weak base through urine by lowering pH of urine.
56Describe first order, zero order, and intermediate kinetics.First order = rate of elim proportional to drug concentration
Zero order: rate of elim is saturable and NOT proportion to drug concentration. e.g. alcohol.
Intermediate kinetics: low doses (first order), high doses (0 order). e.g over-dosing of drug.
57Describe difference between these two graphs.First Order Kinetics = give more drug, bump in concentration till you reach CSS. Doubling dose raises plateau.
Zero Order Kinetics = as you increase concentration of drug, body loses ability to eliminate drug, drug builds up in plasma and reaches saturation point.
58What 3 things happen once drug goes to liver (First pass effect)? What type of admin by-passes First Pass?1) drug may be active metabolite and enters sytemic circulation
2) metabolized, destroyed, eliminated
3) eliminate through bile --> goes to SI --> can be reabsorbed back into liver
Sublingual, terminal portion of rectal, intravenous.
59Define bioavailabilityAmount of drug in systemic circulation divided by amount of total drug administered (this would exclude first pass effect).
60Define half life of drug.Time required to reach 50% of initial value. follows first order and decreases exponentially with time.
61if it takes 5 half lives for drug to be eliminated from body, does that mean that it stops working after 5 half lives.No, depends on the amount of drug given at beginning. dose could be so low that it could stop being therapeutic after 1 or 2 half lives.
62—Distribution - concentration of drug decreases rapidly in plasma. Drug delivered quickly to other parts of body.
Elimination - exponential disappearance of drug from plasma with time. Calculate half life here, time it takes to decrease drug concentration by 50%
63Pathological conditions require dose adjustment as they may increase or decrease half-life. When does this happen?Increase half-life if DECREASE: metabolism (liver disease slows metabolism) , extraction rate (renal disease decreases elimination), renal flow (heart disease decreases filtration rate)
Decrease half-life by increasing: albumin binding (if it binds to albumin, you decrease amount that can be distributed, metabolized and eliminated, so longer half-life).
64Provide an example where: Without change the dosage of the drug, other aspects that simply relate to absorption or acidification or alkalinization of the urine will have a major impact on the drug's concentration, half life and therapeutic benefit of drug administration.Chloropropamide PKs: drug for diabetes
1) charcoal decreases absorption by 90%
2) Sodium bicarbonate: alkinalizes urine, decreases half life and increases excretion of CP by 400%!!
3) Ammonium Chloride (acidification of urine): increases half life and decreases excretion by 80%.
65Define agonist vs. antagonist. define the different types of binding.An agonist is a compound that when it interacts with the cell, it actively changes the response of the cell: can be an active stimulation or an active inhibition
An antagonist is a drug that interacts with the molecular target and just sits there - it doesn’t do anything.
Specific binding: lock and key
Non-specific: binding with elements of cell or tissue. For eg, drug that binds to membrane with high Poil/water coefficient.
Reversible: can couple and uncouple.
Irreversible: drug doesn't uncouple, rare
Competitive: give it at the lowest dose to prevent the lost of the agonist that will be hijacked by non-specific targets such as membranes.
66What is a allosteric ligand? Allosteric agonists? Allosteric inhibitor?drugs that bind to other sites other than the real recognition site. these have a different shape.
stimulatory or positive affects: Allo Ago
or they can sit their and prevent things from happening: Allo inhibitor
67Name energy independent transporters. Describe the first one.Ion channels, transporters, pumps, enzymes.
Ion channels - simple transmembrane, when stim by changes in membrane potential, it opens, ions go from high to low conc. gradient. No ligand Recognition site, no ligand site, no agonist and antagonist.
Blocker: lidocaine (Na ion channel), dihydropiride (Ca channel blocker).
68what is the benefit of transporters?allows different mocs to go from low to high concentration gradient.
Same direction - symport, NT transport, amino acids, glucose transporter
Opposite direction - anti-port, 3 Na for 1 Ca transporter (calcium export).
69describe pumpsallow ions or mocs to go against concentration gradient.
ATP dependant, NOT an exchange. ACTIVE transport.
transmembrane proteins + membrane bound enzymes.
Saturable enzymes-substrate kinetics. (ATP binding, Na/K ATPase, Multi-drug resistance).
70What are MDRs?Multi Drug Resistance Proteins.
- They pump things out of the cell.
- This is one of the processes involved in the resistance of cancer cells to chemotherapy.
- You can give an anti-cancer drug to a patient, gets into the tumour cell, but before it can interact with the DNA and prevent the cell from surviving or replicating, the cytoplasm of the cell fights for its survival and pumps it out of the cell before it works.
- By doing that, the tumour will become resistant to that particular drug.
- This is due to over-expression of MDRs.
71How do drugs interact with enzymes. what are false substrates.The functional interaction between a drug and an enzyme can be of 2 different types:
- It can lead to modify the activity and availability of the enzyme in order to produce an active substance and it can activate also the substrate itself, induce the enzyme (enzyme inhibition, enzyme induction).
- It can simply bind to the enzyme be transformed into a product of very little relevance. By doing that, it is inhibiting the function of the enzyme.
The original drug didn't have any effect either. If we want to inhibit a defect of the drug - if we want to keep it busy doing nothing. We give a false substrate. Usually, the functional interaction between the drug and the enzyme can be of 2 different types. It can modify the activity and the availability of the enzyme to make an active substance and can activate the substrate itself. Or it can simply bind to the enzyme, be transformed into a product of very little relevance, but by doing that, it is inhibiting the action of the enzyme.
72How would you treat an over-growing prosthate driven by DHT?DHT - stimulates growth of prosthate. Males have trouble urinating. There is an enzyme that promotes this activity: 5 alpha reductase.
treatment: give a 5 alpha reductase inhibitor. Finesteraide. inhibits transofrmation of testosterone into DHT.
73Describe how the PDE5 inhibitor works (viagra)?- If you give a drug that selectively inhibits PDE5 selectively, the consequence is that the enzyme (and the blood vessels) is inhibited in those PDE5-rich areas.
- If you inhibit PDE5, that will lead to inhibition of the transformation cGMP to GMP.
- In those regions, those blood vessels are going to dilate. There are regions in the body where the blood vessels are extremely rich, there are many blood vessels in certain parts of the body. If you have an enzyme that is inhibited and that leads to vasodilation, all of the vessels in that organ/region will dilate and the size of the organ will increase.
- The name of the drug is called Sildenafil, known as Viagra.
- To understand the mechanism of action of Viagara,
74Describe the characteristics of receptors?
75what are the two major types of receptors? describe the subtypes.Extra cellular :
1) Ionotropic
2) GPCR
3) Tyrosine Kinase
Intracellular: can be in cyto or nucleus. substrate is highly lipid soluble.
76Describe how ionotropic receptors work.It means that when drugs in a selective manner bind to the ligand recognition site, leads to conformational changes that result in opening of the pore, that will allow a particular ion to go through.
structure: 5 subunits, 2 alpha chains (ligand binding site). All intra membrane, the amino and carboxy terminals are both on outside of cell.
Nicotinic Acetocholine
77Name a GABA allosteric modulator.As allosteric drugs, what happens when you just have the allosteric drug and receptor? Nothing. The allosteric drug needs to have the agonist present. If it is not there, it has nothing to modulate. They help things - they do not cause changes by themselves. Because there is a lot of GABA in the brain, if you give benzodiazepine, it helps GABA in the cells.
Benzodiazepines helps increase the number of openings per second. Every time a GABA molecule is to an alpha subunit, the binding of GABA it will open more often during one second. The consequence: more chloride goes in.
Barbiturate also facilitate the entry of chloride in the cell but it will not increase the number of openings per second. They increase the length of the time the chloride channel
78Describe the GPCR structure and how it differs from ionotropicGPCR - 1000 different types.
amino terminal outside, carboyx inside. 7 transmembrane domains. 3 intracellular loops, third one binds to g-protein. unlike ionotropic (ligand binding site outside), ligand binding site is in a pocket inside the 7 transmembrane domain. Small pore, so ligand cannot be too large.
79explain GPCR signal transduction pathway1) agonist binds to receptor
2) Active change in receptor leads to g-protein activation and initiation of pathway
3) g-protein interacts with adenylyl cyclase (stimulation activates PKA)
4) PKA phosphorylates another protein --> opening of channel
80Describe the interaction between receptor and g-protienG protein - heterotrimeric (alpha, beta, gamma). bound to GDP
1) When agonist binds, results in activation of g-protein. GDP binds to GTP.
2) alpha unit of g breaks from beta and gamma
3) alpha binds to effector protein. breaks down GTP back to GDP
4) alpha goes back to g-protein and attaches to beta and gamma subunits.
81explain the bi-directional control of target enzyme via g-protein. How does this differ in the pathway that regulates calcium?Alpha subunit has Gs and Gq subscripts for the PKA pathways. Agonists that bind to Gs will have a stimulatory effect and activate the cell whereas agonists that bind to Gq ill have an inhibitory response and inhibit the cell.
in the phospholipase C pathways, there are no inhibitory subunits, the only way to inhibit this pathway is to bind an antagonist to the receptor to prevent binding of agonist.
1) PLC --> activates PKA --> DAG --> PKC --> ion channels (Ca + K)
2) PLC --> IP3 --> release of calcium from reticulum --> contractile effects
82T/F: Heterogeneity of G-proteins allows different receptors to exert opposite effects on a target enzyme.True
83What is the end result of stimulation of GPCR?changes in gene expression
84Name the three enzyme-linked receptors we discussedRTKs, Rs/TKs, RGCs
85How do enzyme linked receptors work?receptor linked to enzyme. agonist activates receptor which activates attached enzyme which interacts with intracellular substrate to initiate signal transduction.
86Describe kinase linked receptor (RTks) pathway. Provide important examples of these receptors in body.1) Binding recognition site on the outside transmembrane domain. The ligand recognition site is readily available on the outside of the cell so this is going to allow very large molecules such as insulin itself, growth factor themselves, thousands of molecular weight to dock onto
2) Agonist binding causes dimerization
3) Autophosphorylation of the intracellular domain of each receptor.
3) SH2-domain proteins then bind to the phosphorylated receptor and are
themselves phosphorylated
4) Activation of RAS/RAF/MAP pathways
5) activation of Transcription factors (TFs)
examples: EGF, NGF, insulin receptors
87What kinds of pathways are activated by growth factors vs. insulin? Describe how cytokine receptors (serine/threonine) receptors work? What happens when we inhibit the S/T receptor pathway?Growth factors vs. insulin - there is the existence of a dimer prior to the binding of agonists and activation of he MAP Kinase pathways whereas in others, like the cytokine receptors is the activation of the Jak Stat Pathway - formation of a dimer that is going to influence gene tran
Cytokine Receptors use the JAK Stat pathway:
These receptors do not have a catalytic domain
- The Stat dimer has two Nuclear Localization Signals (NLS)
- Moves into the nucleus, binds to promoter sequences
- Activates gene transcription of selective genes.
Inhibition results in anti-inflammatory effect.
88Describe an important mechanism that links to Kinase linked receptors - Guanylyl Receptor CyclaseNO receptors. Activation leads to dilation of blood vessels and relaxation of smooth mm.
Pt takes nitrates, increases product of NO, NO binds to receptors and causes things above.
89What is the most crucial characteristic for drugs that bind to receptors?They have to be somewhat lipo-soluble
90Describe two classes of intracellular receptors.
91How can we use glucocorticoids to ellicit an anti-inflammatory response?GC receptor: We have a Class I receptor bound to a Heat Shock protein. The glucocorticosteroid is going to diffuse through the membrane easily (highly liposoluble) and will bind to these receptors, to the end coupling of the chaperone protein and complex with a dimer where it will interact with DNA and will lead to changes in gene expression. In this case, this might result in an inhibition of certain gene and production of proteins. If we have an inflammatory process, if we are talking about genes that mediate inflammation, the more excitation that occurs, the more inflammation occurs.What we want to do is use glucocorticosteroid and use their anti-inflammatory properties to put a stop on the expression of those enzymes.
- Glucorcorticosteroid: Translocation to the nucleus
- Binds to the receptor sequence,
- Inhibit certain inflammatory mediating gene (anti inflammatory properties) OR it can have a hormonal effect (we will discuss this during endocrine system, metabolic roles of corticosteroids). It depends on the receptor
92Describe how class II receptors regulate inflammatory response. How can glucocorticoids modulate this response?CLASS II RECEPTOR that is going to be activated by transcription factors inside the cell. There are no agonists or antagonists here. It is happening inside the cell.
- This transcription factor has an excitatory effect on the receptor site and will increase the production of mRNA in certain proteins. These proteins can be cytokines. The more excitation of these receptor sites occur, the higher the production of mRNA and the higher production of proteins (which are cytokines).
- Cytokines have pro-inflammatory properties. The more these things happen, the more inflammation occurs. If we want an anti inflammatory effect, we have to block this process.
- One way is to have glucocorticosteroids bind to their own receptors. In this case, where there is a binding of a complex between a steroid receptor and an agonist, this will leads to the binding of the transcription factor. This is described in the literature as “cleaning up transcription factors”. If you clean up or block or sequester the transcription factors in the nucleus, the
93Which of the three drugs have the highest efficacy/potency? Define efficacy vs. potency. What does the flat line represent? At what concentration do we get the maximum effect of A and B?A/B = full agonists max effect of 100%
C = partial agonist = ME is 1/2 of A and B
A is more efficacious than B. In order to have same efficacy, we need to give more B.
10-7 for max effect (A and B)
Efficacy = Emax (100% of drug's effect)
Potency = dose related. Amount you need to give to be efficacious.
Drug A is more potent than B b/c you need to give less of it.
Flat Line - represents concentration that produces max effect, beyond which there is no effect regardless of additional dose
94Which drug is safer? What does a steep dose response curve indicate?The one with the wider therapeutic ratio (Drug A). Threapeutic ratio is the gap between the desired and adverse effect. (B) the likelihood of adverse
effects at therapeutic doses is increased because the curves are not well separated.
a steep dose-response curve for adverse effects is especially undesirable, as
it implies that even small dosage increments may sharply increase the likelihood of
toxicity
95Describe the diff between TW and TI.TW: Range of therapeutically safe and effective concentrations.
TI: Ratio between the 50% value on the Toxicity curve (TD50) and the 50% value on the efficacy curve (ED50). TI= TD50 / ED50
96Describe specific. vs. non-specific binding to receptor.Specific and non-specific relate to single drug.
Specific: drug and own selective receptor. as you give more drug, the amount in body increases until you reach flat line due to saturation of all receptors.
Non-specific: drug goes other places (liposoluble drug will cross membranes). Amount of binding is a sum of all the different individual binding. As you give more drug, concentration in body keeps increasing in the case of lipo-soluble drugs bc there is limitless fat in the body. No saturation point.
97What type of binding is seen here? Describe it.Reversible antagonist binding to receptor. We have a competitive study.
- We give our agonist (in a laboratory setting) which could be adrenaline.
- We can see that the response is an increase in blood pressure.
- If I give very little reversible antagonist, some receptors are blocked by the antagonist. When I put in the agonist, it is going to complete with the antagonist and the agonist displaces it and continues to do what it did before. I increase the concentration of the antagonist 10 times. After I do this, I introduce the agonist. It is more difficult for the agonist to displace the antagonist since more antagonists are interacting with the receptors. If I keep increasing the agonists, eventually I will have enough agonists to push out the antagonist and do what it needs to do.
98What type of binding is here.If I add a bit of irreversible antagonist, there will be less receptors available for the agonist because the antagonist are irreversibly bound to the receptors.. If I put more antagonist, I will have more receptors out of commission forever because they are irreversibly blocked by the antagonist so I have to add more agonist - with a difference: The number of receptors available for the agonist to do what it usually does is going to I need a lot more antagonist to do what it usually does is going to be decreased significantly because most of them will be irreversibly blocked. That is why our effect decreases more and more. The less receptors are available to interact with the receptors and the more blocked by irreversible
99What does C and D represent?C = non-competitive agonists - allosteric activators.
GABA A receptor = Benzodiazepines (Diazepam, Valium®)
Barbiturates (Phenobarbital)
D= non-competitive antagonists
glutamate NDMA receptor
Memantine (Ebixa®)
100What are the 3 main mechanisms targeting receptors
101How does the cell protect itself from over-stimulation by agonist?Repeated stimulation by agonist --> reduce response via densensitization/refractory period (phosphorylation of receptor for some period of time). Takes seconds-min to recover.
Stimulation Persists: cell protects itself from overstimulation by internalizing the receptors through endocytosis. They can be re-sent to membrane if abnormal stimulation disappears. Takes some min to recover.
If stimulation STILL persists, internalized receptors are destroyed. Takes days to recover from. Absolute decrease in number of receptors.
102Describe the functional/adaptive mechanisms that prevent overstim by a drug.
103Define bioavailability. How is bio availabilityBioavailability is the fraction of unchanged drug (fu) reaching the systemic
circulation, after administration by any route.
If there is decreased effectiveness of the p-glycoprotein activity, then there is a higher availability in the brain. There is a leakier, less permeable BBB that will allow a higher concentration of the drug to get in.