Flashcards
CHEM 430 midterm
Cards in this deck (126)
- 1What does negative potential mean and what is this maintained by?Intracellular environment negative relative to external.
Maintained by K+ leak channel - 2Name 4 clinical applications that target cell excitation as treatment approach.1. block nerve conduction as local anesthesia
2. reduce nerve cell excitability in epilepsy
3. reduce vascular smooth muscle tone to decrease BP
4. suppression of aberrant excitation in cardiac arrythmia - 3Why would nonexcitable cells have membrane potential? (2 reasons)1) PMF for OXPHOS
2) active transport & cmpd uptake - 4Define resting potential and action potential in the context of excitable cells.Resting potential = -70 mV, cell default membrane potential based on ion gradient on both side; excitable cells only
Action potential = transient reversal of membrane potential - 5Other than neurons, name 3 types of excitable cells and briefly describe their synapses.1) Skeletal muscle - motor neuron
2) Gland cell - neuron
3) Heart muscle - pacemaker via electrical synapses & worker cells - 6What are the 2 forces that generate diffusion potential across membranes?Colomb force and entropy
- 7For K+, Cl-, Na+, Ca2+, name their relative concentration in cytosol vs. extracellular + flow dir.K+ : high intra, low extra > OUT
Cl- : low intra, high extra > IN
Na+ : low intra, high extra > IN
Ca2+ : VERY low intra, high extra > in - 8Which ion channel is the most regulated?Na+ channels most regulated because this controls AP
- 9Which channels open to make membrane potential more + ? More -?More +: NaV, CaV
More -: Cl-, K+ - 10Describe how voltage-gated sodium channels sustain & spread action potential (4 stages).1) Nearby cells get depolarized
2) Na channel open, steep influx of Na+
3) K+ channel slowly open, repolarizes cell
4) Na+ close - 11How does voltage gated potassium channel extinguish action potential?By letting potassium out to repolarize the cell
- 12Differentiate between the depolarization of pacemaker vs. worker cells.Pacemaker: spontaneous drifting lead to opening of CaT, repolarized by K+ channel
Worker: depolarization via CaL, repolarization via SLOW Kv (weird AP shape) - 13How does planar lipid bilayer work?Insert purified channel to lipid bilayer
Apply voltage & measure current across channel - 14How does the patch clamp technique work?Observe channel in natural environment by using whole cell; glass pipette seals a patch of the membrane containing channel & a current is passed through to observe ion flow
- 15What’s the difference between fast and slow block?Fast block - blocks the active NaV conformation; reversible
Slow block: blocks inactive state of conformation; declay channel reactivation - 16How are diethylamine and phenol used to demonstrate the fast and slow block action of lidocaine on NaV channels?Diethylamine & phenol ~ to lidocaine parts
- 17How do Katp channels in smooth muscle cells shut down excess contraction?XS muscle contraction deplete ATP > dissociated from sulfonylurea receptors, opens Katp channels>hyperpolarize cell and prevent muscle contraction
- 18How do Katp channels in beta cells regulate insulin secretion? Potential drug target?Uptake of glucose makes ATP > attach to sulfonylurea receptor > close Katp > depolarize the cell > intiate Ca2+ mediated insulin release
- 19Name 2 types of Ca2+ channels that control striated muscle contraction & differentiate.Dihyropyridine receptor (DHPR) - L-type Ca channel
Ryanodine Receptor (RyR) - Ca2+-activated Ca2+ channel on ER membrane - 20Differentiate entry of Ca2+ in heart vs. skeletal muscle cells.In heart muscle cell, entrance of Ca2+ through DHPR is required to open RyR, which in turn induce contraction.
In skeletal muscles, DHPR conformation change alone is enough to trigger RyR release of Ca2+ to induce contraction. - 21What are transient receptor potential channels? Activators? Functions?Fxns for sensory perception
Activated by physical stimuli and conduct multiple ions (hydrated form)
also some ligands (ex. capsaicin) - 22Briefly explain functional cycle of Na/K ATPase.1. ATP-bound, take-in 3 Na+
2. Self-hydrolyze ATP, release 3 Na+ out
3. Take in 2 K+
4. Release Pi & bind ATP, release K+ in - 23Name how Rb+ is used to elucidate the phosphorylation states of Na/K ATPase.Rb+ mimics K+ but plugs the channel > addition causes Na/K ATPase to deP and decrease in labeled form, which was present when there is only Na+
- 24Differentiate between presynaptic feedback vs. retrograde feedback.Presynaptic - neurotransmitter goes back to another receptor on presynaptic neuron to prevent release of more neurotransmitter
Retrograde - post-synaptic neuron releases a neurotransmitter to inhibit presynap - 25Name & describe two types of summation of postsynaptic potentials.Temporal - firing frequency det. AP
Spatial - inhibitory vs. excitatory presynaptic neuron summation det. firing of post-synaptic neuron - 26Name 2 major families of major neurotransmitter receptors and types under each.1. Ligand-gated channels (Cys loop, purine X receptor, glutamate)
2. GPCR (alpha, beta, muscarinic) - 27Describe how photoaffinity of TDBzcholine is used to determine the binding pocket of Ach receptors.Photoactivation of TDBzcholine forms covalent adduct with receptor > label detection = receptor adduct; fragmentation to determine exact ligand-binding site
- 28Draw Ach receptor function cycle – what drives the unidirection?Resting, bound > Open, bound > Inactivated bound > Inactivated, free> resting, free
Driven by degradation of Ach neurotransmitter - 29Name 2 excitatory and inhibitory receptors in cys-loop family.Ionotropic
Excitatory: nAchR, 5-HT3 serotonin
Inhibitory: GABAa, Glycine - 30Name types of synapses for both sympathetic and parasympathetic systemSymapathetic: 1) nAChR, 2) a/B-adrenergic
Para: 1) nAChR, 2) muscarinic - 31Explain the concept of a “false transmitter”?A false transmitter inhibits the release of actual neurotransmitter from vesicle; once released from presynap, they also feedback inhibit the presynaptic neuron to further decrease activity of synapse
- 32How can MAO be inhibited and why is it inhibited?MAO can be inhibited via mechanism-based inhibition by forming covalent adduct.
MAO degrades neurotransmitter from catecholamine synapse > increase life time of monoamine transmitter to treat depression - 33Name 3 major types of hormone receptors.1. Nuclear receptors (steroid, thyroid)
2. Tyrosine Kinase receptors (insulin, GH, growth factor)
3. GPCR (ppt hormones; ep/norep) - 34List the glands and the respective hormones under the control of anterior pituitary.Thyroid > T3/T4
Adrenal gland > cortisol, aldosterone, androgens
Testicles/ovaries > estrogen, androgens, progestins
mammary gland > prolactin - 35Illustrate regulatory patterns in the hypothalamus pituitary axis for cortisol and growth hormone.GHRH > GH > IGF-1; somatostatin inhibits GH
CRH > ACTH > cortisol
Both are feedback inhibition loops - 36Name the hormones under the control of posterior pituitary.2 ppt hormones
vasopressin (antidiuretic)
oxytocin (induce labor, breastfeeding) - 37Name 2 types of thyroid hormones and which is more powerful.T3 and T4
T3 is more powerful form - 38Knowing thyroid hormone induce both B-adrenergic and uncoupling protein, what will happen?B-adrenergic receptors in heart and muscle, so expect increase HR
Uncoupling protein increase ETC activity without ATP production > increase heat prod (sweating) - 39Which enzyme iodinates and couples Tyr to make thyroid hormones?Thyroid peroxidase
(couples Tyr side chain of thyroglobulin) - 40How do goiters occur and how can they be treated?Hypothyroidism > enlargement of thyroid gland. Treat via iodine supplementation
- 41How can hyperthyroidism result and how can they be treated?From autoantibodies against TSH-receptor/hormone-producing tumors
Treated: 131I, thyroid peroxidase inhibitors (methimazole) - 42Give the classes and major members of the steroid hormones + glands they are from.Glucocorticoid, cortisol (adrenal)
Mineralcorticoid, aldosterone (adrenal)
Androgens, testosterone, dihyro (testicles)
Estrogen, estradiol/triol (ovary)
Progestins, progesterone (ovary, placenta) - 43Differentiate between transactivation vs. transrepression.Transactivation - hormone-bound nuclear receptor binds DNA seq & act as transcription factors to increase expression
Transrepression - hormone-bound nuclear receptor binds proteins (i.e. TFs) to decrease transcription of certain genes. - 44Name classes of hormones belonging to adrenal steroid hormone and functions.Glucocorticoid - metabolic regulation
Mineralcorticoid - control of Na/K balance & elimination in kidneys
Androgens - precursors for gonadal androgen & estrogens - 45Which enzyme prevents non-specific mineralocorticoid receptor activation and how does it work?11-B-hydroxysteroid DH
Oxidizes cortisol to cortisone to prevent them from binding MR in kidney epithelia to prevent XS retention of Na & excretion of K - 46What happens if aromatase is inhibited? Use?Aromatase responsible for making estrogen from testosterone. Inhibitor useful in treating estrogen-breast cancer
- 47Describe the role and processes done by osteoblast.Osteoblast responsible for building bone matrix. Lays down collagen that forms fibrils, which is covered with PPi to inhibit premature Ca2+ deposition. Alk Phos. cleaves PPi and initiates bone matrix formation.
- 48Describe the role and processes done by osteoclast.Osteoclast breaks down bone matrix.
Osteoclasts bind to bone matrix, seal a patch and secrete H+ that dissolves it. Ca2+ and Pi released from it then taken into blood. - 49What’s the major hormone to increase bone desorption and how does it work?Parathyroid hormone (PTH)
Released via decrease in blood [Ca2+], promotes Ca2+ retention and Pi elimination from kidneys; promotes activation of VitD - 50What are the major hormones to decrease bone desporption?Calcitonin - via C cells, promotes Ca2+ & Pi deposition in the bone
Calcitrol (VitD) - promote Ca2+ & Pi uptake via intestines; inhibit PTH secretion
Estrogen - sustain bone matrix - 51Name the long vs. short-term control of bone marix hormones.Short: PTH vs. Calcitonin
Long: Calcitrol, estrogen - 52How do bisphosphonate drugs work?Biphosphonates target osteoclasts. They resemble pyrophosphates, which are taken by osteoclasts > inhibit FPP synthesis in the cell & lead to apoptosis
Overall prevent bone matrix resorption - 53Name the 3 ways by which drugs affect their receptors1. Mode of binding: reversible/covalent
2. Bind site: ortho vs. allosteric
3. Fxnal effect: activation vs. inhibition - 54What’s the Scatchard plot, why is it used and how do you interpret it?Semi-log graph, logged [ligand]
n (R abundance) = y-axis, k=slope
Straight line for 1 type receptor; curved >1 type receptor - 55Illustrate reversible and covalent receptor inhibition as Y (receptor saturation) vs. [ligand].Reversible = right-shifted curve
Covalent = vertically compressed curve - 56Write equation for competitive inhibition. Why does this explain receptor occupancy curve shifts right?Y = [L]/[L] + K'
K'>KL, so curve is right-shifted - 57Write equation for covalent inhibition. Why does this explain vertical compression of receptor occupancy graph?Y =(L/L+K)(Runmod/Rtotal)
Runmod < Rtotal, vertical compression - 58Look at graph of tolazoline and phenoxybenzamine, which type of inhibition is each?Tolazoline = right shift > reversible
Phenoxybenzamine = vertical compression > covalent - 59How does phenoxybenzamine block receptors covalently?Phenoxybenzamine block a-adrenergic R via reacting with Cys side chain to form covalent adduct
- 60Differentiate between effect of full agonist, partial agonist, antagonist, inverse agonist and neutral antagonist wrt two state model.Full: affinity for active state, 0 for inactive
Partial: affinity for active>inactive; partial acitivty
Inverse: affinity for inactive> active, decrease spontaneous activity
Neutral: affinity active = inactive; doesn't change equilibrium - 61Plot dose-effect curve of two state model with reference to full & partial agonist, inverse agonist, neutral antagonist. (Y vs. [L])Full = max activity
Partial = partial max. activity
Inverse = decrease activity from basal
Neutral = flat basal activity
*Assuming receptor has some activity state w/out ligand - 62Look at graphs for 5-HT1A, 5HT2B, Dopamine, what type of action is aripiprazole taking?Aripiprazole is partial agonist for 5HT1a, inverse agonist for 5 HT2b, maybe neutral antagonist for dopamine (dunno)
- 63Name 4 receptor behaviors not explained by 2-state model.1. Oligomers & cooperativity
2. Agonist-specific coupling
3. Refractory states
4. B-arrestin-biased ligands - 64Explain cooperative behavior of oligomeric receptors. What’s the effect on receptor activity?Individual subunits bind L via mass-action kinetics but doesn't change state individually. Change in conformation is in concert > lead to sigmoidal curve, lower signal: noise ratio.
- 65Explain agonist-specific coupling. Example?More >1 active receptor conformation state linked to 2 diff adapters > 2 diff effects.
Ex. 5-HT2 receptors that bind 2 G proteins - 66Explain receptors with refractory states. Example?Receptors has a state that's bound to ligand but functionally inactive, also in resting but activiable state
Ex. nACh receptor - 67What’s receptor reserve? How does this relate to biochemical cascade dose-effect?RR = amt of R that can be KO'd without affecting the effector activity
[R] directly related to biochem effect, depending on population of native vs. overexpressed receptor - 68Differentiate potency vs. efficacy.Potency = lowest [drug] that elicits effect
Efficacy = extent of drug effect - 69What’s the therapeutic index and what does it mean?TI = drug toxic/drug effect
Used to det. range of dose that optimize betwn efficacy vs. toxicity - 70Briefly describe 3 stages of drug transport.1. Absorption - uptake into blood plasma
2. Distribution - equilibration of drug between blood and rest of body
3. Elimination - excretion/metab. inactivation - 71Name 3 routes of application, adv/disadv associated.1. Oral - convienience; multiple barriers
2. Intravenous - no barriers; risk of infection/allergy
3. Pulmonary - fast, limited use - 72Name 4 possible locations of drug targets & examples.1. Inside circulation, inside cell
2. Inside circulation, outside cell
3. Outside circulation, inside cell
4. Outside circulation, cell surface - 73Describe difference between regular capillary vs. brain capillary; relationship to drug distribution?Reg. capillary: 1 layer, fenestrated endothelium allow solute exchange
Brain: 2 layers, unfenestrated endothelium via tight junction + glial cells seal - 74How does intestinal epithelium act as barrier to drug absorption?Intestinal epithelium has P450 that inactivate drugs + ABC transporters that extrude drugs
- 75How are MOST drugs transported in the body?Passive diffusion
Non-ionic diffusion - 76What’s the ideal polarity of drugs and why? How can this be achieved?Hydrophobic - can cross membrane but not to hydrophobic to get stuck
Achieved via removing polar fxnal gps - 77Why is heroin much more potent and addictive than morphine? (hint: absorption?)Heroin can cross BBB (acetylation), while morphine can't; more addictive and potent
- 78What’s non-ionizable diffusion? How is this useful?Transport of ionizable drug in nonionizable form
pH adjustment can change ionic state of drug to prevent accumulation/activation - 79How does gastric acid promote the accumulation of acetylsalicylic acid in cells of mucous membrane?ASA protonated in acidic pH > cross membrane via non-ionic diffusion > deprotonated & ionic in alkaline pH in cytosol to prevent accumulation in gastric mucosa > effect
- 80What are ABC transporters (traits) and where are they located? Why are they problematic wrt drugs, especially chemotherapy?ATP-binding cassettes. Located in SI, liver, kidney, BBB. Extrude drugs > contributes impenetration & chemo drug resistance
- 8112. How can drug uptake in the brain be increased? (hint: ABC transporters)By inhibiting ABC transporters
- 82How is L-DOPA transported in the brain and how can this delivery be optimized?Transported via Tyr transporter > converted to dopamine via decarboxylase
Optimize via peripheral L-DOPA decarboxylase inhibitor - 83Briefly diagram the portal circulation (weird).To liver:
1) Liver artery (oxygenated)
2) Portal vein (from GI, partially oxy)
Out liver:
Liver vein (deoxygenated) - 84What are the 2 fates of drug in liver lobule? What is the function of liver cell?1) Drug is taken up into hepatocytes
2) Drug enters bile via bile duct - 85Define first-past effect.% of drug converted to metabolite via portal circulation before reaching systemic
(i.e. partial inactivation, propanolol) - 86Name 3 compartments of drug distribution. If in circulation, what is drug likely doing?1) Mostly in circulation (large drugs)
2) In interstitial space (hydrophilic)
3) In fat (lipophilic)
If in circulation, likely bound to serum albumin - 87Explain volume of distribution (Vd) and what the values will mean.Vd = mol drug/[drug] plasma (L)
Low Vd = in circulation; quick elimination if not bound to protein
high Vd = in fat, slow elimination - 88Illustrate elimination route of hydrophilic and hydrophobic drugs.Hydrophilic = renal excretion (if small)
Hydrophobic = converted to hydrophilic in liver then renal excretion - 89Name 4 stages of urine processing by the kidney.1. Ultrafiltration
2. Solute reuptake
3. Water reuptake
4. Solute secretion - 90Outline function of the glomerulus, proximal tubule, loop of Henle, distal tubule.Glomerulus - filtration via hydrostatic P
Proximal tubule - active solute reuptake
loop of Henle - water reuptake via salt gradient of interstitial space
Distal tubule - fine tune pH, salt content - 91What drives glomerular filtration?Difference in hydrostatic P > high in arteriole, low in capillary
So net filtration - 92For which stages can drugs be substrate?Filtration, reuptake and secretion
- 93How does drug’s rate of urinary excretion depend on its membrane permeability?Permeant = Curine ~ C interstitial; excretion ~ vol. urine
Impermeant = nurine = nfiltrate
excretion NOT dependent on urine vol; rate of elimination ~ GFR - 94What does inulin clearance measure and why?Measures GFR
Quantitatively filtered without reuptake or secretion because it's a polar molecule; impermeant & retained in urine - 95What does renal clearance measure and mean?Renal clearance measure vol. of blood plasma cleared of drug per time
i.e. how effectively kidney eliminates drug - 96Under what circumstances can drug half-lives be accounted for by GFR?Low protein binding and in circulation
- 97Differentiate between glomerular filtration rate (GFR) vs. renal plasma flow (RPF)GFR = Vfluid filtered from renal glomerular capillaries per time
RPF = V blood delivered to kidney per time (measure via pAH that's quantitatively secreted in single pass of blood through kidney) - 98How can one prevent drug accumulation caused by repeated-drug application?Use initial large loading dose to get therapeutic lvl then use smaller repeated dose
- 99Name 4 types of reactions in drug metabolism1. Oxidation
2. Reduction
3. Conjugation
4. Hydrolysis - 100Define enterohepatic cycling + diagram to illustrate the process.Process of reuptake & cycling back to liver via portal vein for repeated round of conjugation (i.e. repeated transformation before renal excretion)
- 101Does hydrophobicity predict the extent of metabolism? Why?No, because most drugs undergo some type of transformation before elimination, hydrophilic + hydrophobic
- 102Name 2 enzymes in each phase I and phase II metabolism & reactions they perform.Phase I - intro of reactive gps (P450, oxidoreductase)
Phase II - conjugation of reactive gp (sulfotransferase, GST) - 103Where are CYP450 enzymes and what types of reactions can they do? Why can they do so many? (hint: BIOL 439)Phase I oxidative metab. enzyme with broad substrate range.
Heteroatom oxidation, dealkylation, carbon oxidation, epoxide formation - 104How is drug metabolism transcriptionally induced? Overall effect?Drug bind preganolone X receptor (nuclear), diffuse into nucleus, bind xenobiotic response elements (XRE) & induce transcription of metab. enzymes to increase OVERALL drug metab.
- 105Name 4 key possible phase II metabolism reaction types.1) Glutathione, GST
2) UDP-glucuronide, glucuronic acid, UDP-glucuronosyl transferase
3) Sulfate, PAP, sulfotransferase
4) Acetylation, acetyl-CoA, N-acetyltransferase (NAT) - 106How is morphine metabolized? What does this indicate wrt to drug metabolism?Skips phase I & directly conjugated.
If reactive already present then skips phase I of metab. - 107Use hepatic metabolism of acetaminophen to explain why excess ingestion is a problem.Acetaminophen undergo phase I > NAPQI (quinone) > react readily with glutathione.
OD leads to glutathione depletion in liver, fatal - 108Explain how GST enzyme can help to activate anticancer drug canfosfamide.Canfosfamide react with GST, which cleaves it to get alkylatin drug that kills cell.
(Target tumors that overexpress GST to confer resistance) - 109What’s N-acetyltransferase? Is this a phase I or II enzyme?NAT = acetylation
Phase II enzyme - 110Explain how arylamine carcinogens can be metabolically activated.Hydroxylated by P450 followed by NAT/ST, eventually lose acetate to form electrophile that react with biomolecules
acidic urine = deprotonated GST > increase toxicity - 111What phase is reductive drug metabolism? Responsible enzymes?Phase I
Enzymes are random (no specific enz) - 112Use redox cycling and reductive metabolism to explain why isouramil can lead to toxicity.Isouramil engages reacts with oxygen and consumes glutathione and NADPH > depletion of glutathione lead to accumulation of H2O2 which can form ROS to dmg biomol
- 113What is favism and why does G6PDH cause this? What’s the broader application of this consideration? (hint: think malaria relevance)Hemolytic anemia w. fava bean
G6PDH deficiency lead to inability to regenerate reducing equiv NADPH > no protein replacement, Hb spill into blood
usually present in malaria-endemic countries
Since antimalaria drugs redox cycles > need to consider this - 114How can reductive metabolism be exploited in therapeutics?Cancer cell = reducing env
Prog drug can be activated via nitro reduction + acetylation > activate 2 alkylation groups to crosslink DNA and kill cell - 115Describe the general GPCR structure.7 transmembrane helices, with CT tethered via FA chain to membrane
Extracell. NT, intracell. CT
Few conserved motifs essential for activity - 116Describe the general GPCR activity cycle.1. GPCR activated
2. Gaby bind GPCR > Ga exchange GDP to GTP
3. Ga & by dissociate > go to effectors
4. Ga self-hydroylze GTP
5. GDP allow reassociation of heterotrimer - 117Explain how FRET can be used to detect G protein bind to adenosine receptor and dissociation from it.Association: CFP on Gy, YFP on GPCR
Dissociation: CFP on Ga, YFP on Gy - 118Which is more diverse – G-protein/GPCR?GPCR more diverse > multiple converge on 1 G protein to trigger same intracellular response
- 119Describe adenylate cyclase pathway of GPCR.Ga activates adenylyl cyclase > makes cAMP > activate PKA to P' stuff
Gby binds Katp > opens > hyperpolarize cell - 120Describe phospholipase C cascade of GPCR.Active Ga cleaves PIP2 > IP3 + DAG
IP3 activate ER Ca2+ channel > release Ca2+ > calmodulin-dependent contraction
DAG activate PKC > P's stuff - 121How does NK1 and NK3 GPCR chimers illustrate the binding mechanism of experimental drug CP96354?NK3 conserved seq on NK1 decreased drug inhibition; NK1 conserved seq on NK3 increased inhibition
Seq exchanged essential for ligand binding on GPCR - 122What type of activation does protease-activated GPCR undergo? How to deactivate?Irreversible > proteolytic cleavage of NT domain binds ligand-binding site on GPCR
Inactivation via endocytosis ONLY - 123What are the advantages of GPCR oligomerization?Cooperativity
novel ligand specificity
diff mediator and reinforce/inhibit each other at cell surface (decrase noise in cell) - 124Explain the experiment that characterized the functional specialization of GABAb receptor heterodimers.Replacing transmembrane helices vs. NT tail of heterodimer affected ligand-bind vs. G-protein activation
- 125Name pharmaceutical applications of bivalent agonists and monovalent ligands. Are heterodimeric drugs feasible?Bivalent agonist = stretch effect on mAChR
Monovalent = selective activation of heteroligomer (similar to agonist-specific coupling)
Heterodimeric not feasible since need to bind correctly and simultaneously - 126What is tachyphylaxis and the mechanism? What are the potential targets in this pathway? (2)Tachyphylaxis = partial desensitizationo f GPCR drug due to B-arrestin deactivation of GPCR
Targets: 1) inhibit B-arrestin, 2) inhibit GPCRkinase
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- Chemistry Flashcards on CHEM 430 midterm, created by Flora Dong on 24/02/2018.
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