8/31/17

Question 1

Contents of the apical domain of epithelial cells

Answer 1

Enzymes
Receptors
Ion channels
Carrier proteins
Special structures: microvilli, sterocilia, motile cilia, nonmotile cilia

Question 2

Microvilli

Answer 2

Finger-like extensions of the PM and cytoplasm

Increase absorptive SA of the cell

Brush border in tubules, striated border in intestines

Actin filaments anchored to a terminal web of myosin

Question 3

Stereocilia

Answer 3

Long, immotile microvilli

Hair cells of inner ear, epididymis, and vas deferens

Serve as mechanoreceptors

Made of actin

Question 4

Motile cilia

Answer 4

9+2 arrangement of microtubules attached to a basal body

Sliding movement is initiated by dynein arms

Forms mucociliary escalator

Nodal cilia: found in embryo, responsible for left/right asymmetry of organs

Question 5

Kartagener Syndrome

Primary Ciliary Dyskinesia

Answer 5

Recessive disorder of motile cilia

Defect due to loss of inner or outer dynein arms, leads to uncoordinated beating

Poor mucociliary clearance leads to chronic bronchitis and also pneumonia and bronchiectasis

Sinusitis that can cause loss of smell, hearing loss

Immotile sperm that can cause infertility

Impaired nodal cilia leads to situs inversus where organs are mirror images of normal

Question 6

Primary cilia

Answer 6

Immotile 9-0 arrangement with no dynein or inner doublet

Found in kidneys

Mechanoreceptors that passively bend in response to fluid flow and create Ca2+ influx

Polycystin-1 and 2 genes make them up

Question 7

Autosomal Dominant Polycystic Kidney Disease

Answer 7

Mutations for the polycstin genes of primary cilia

Enlarged cystic kidneys and can get cysts elsewhere like in pancreas

Question 8

GLP-1

Answer 8

Made from proglucagon in the intestinal L cells

Levels decreased in type II but respond to it

Decrease gastric emptying and appetite
Increase beta cell proliferation, decrease apoptosis

Neuroprotective, cardioprotection, and promotes bone formation

Question 9

GIP

Glucose-dependent Insulinotropic Peptide

Answer 9

Secreted by K cells in jejunum

Secretion not decreased in type II but resistant

Similar effects to GLP-1

Not a therapeutic target

Question 10

GLP-1 analogues (incretin mimetics) vs. DPP-4 inhibitors (incretin enhancers)

Answer 10

Incretin mimetics: Exenatide from Gila Monster and Liraglutide, subcutaneous injections, weight loss, nausea

Incretin enhancers: vildagliptin and Sdagliptin, oral administration, increase GLP-1 levels 2-3 fold, also inhibit cleavage of other proteins from DPP-4, weight neutral, no side effects

Both don’t increase hypoglycemic episodes since effects are glucose-dependent, don’t take if have severe renal probs

Question 11

Counterregulatory Hormones

Answer 11

Glucagon, catecholamines, growth hormone, cortisol

Increase glycogenolysis, gluconeogenesis, lipolysis, hepatic ketogenesis
Decrease peripheral glucose uptake

Growth hormone and cortisol have dampened effects compared to the other two

Question 12

Impaired defense against hypoglycemia in type I

Answer 12

After 5 years glucagon response to hypoglycemia is lost and rely on epinephrine from adrenal glands

Hypoglycemia-associated autonomic failure:
Epinephrine response gets blunted after recurring hypoglycemia

Prevention of hypoglycemia can rescue impaired counterregulatory hormone defect, defect is less common in type II

Question 13

Diabetic Ketoacidosis

Answer 13

Need-
1. Insulin deficiency: leads to increased FA delivery to liver and subsequent movement into mitochondria

2. Counterregulatory hormone excess: increases CPT II and conversion to ketone bodies

Characterized by Hyperglycemia and ketonemia

Increased water in urine for higher glucose and ketones lead to dehydration that causes low blood pressure and shock.

Ketones only come from liver, can cross BBB unlike FAs

Question 14

Clinical symptoms of diabetic ketoacidosis

Answer 14

Nausea, vomiting, thirsty, abdominal pain, shortness of breath

Tachycardia, dehydration, hypotension, respiratory distress, lethargy, possible coma

Question 15

Pharmacokinetics

Answer 15

Time-dependent changes of drug conc. in body following drug administration

Looks at conc. in plasma, target tissues, etc.

Question 16

4 Factors affecting pharmacokinetics

Answer 16

Absorption

Distribution

Metabolism

Excretion

Question 17

Drug Absorption

Answer 17

Most drugs absorbed by passive diffusion, not saturable, first order kinetics

Need neutral form to pass membranes, weak acid start neutral but weak base needs to be deprotonated to cross

High pH makes harder to absorb weak acids, easier to absorb weak bases

Question 18

Bioavailability

Answer 18

Oral drugs exposed to liver and are metabolized before reach rest of body (first pass effect)

IV administration directly enters systemic circulation and has access to rest of body

Bioavailability = area under curve (oral) / area under curve (injected) * 100
Time vs. plasma conc.

Fraction of orally administered drug that reaches systemic circulation

Question 19

Factors for Bioavailability

Answer 19

Some drugs not stable in acidic environment

Not efficiently absorbed in the GIT

Microorganisms can metabolize

P450 enzymes in GIT metabolize some drugs

First pass Effect in liver

Question 20

Drug Distribution blood flow

Answer 20

Blood flow: brain, liver, and kidneys have higher blood flows than muscle, skin, and fat

Capillary Permeability: endothelial cells in liver have large fenestrations for drugs, brain has tight junctions that limit

Binding of drugs to plasma proteins and tissues is reversible/nonselective and slows drug transfer

Question 21

Two compartment model of drug distribution in plasma after IV

Answer 21

Alpha Phase: initial rapid decline in plasma drug conc. due to distribution from circulation into the peripheral tissues, ends when form pseudo equilibrium of drug conc. between circulation and peripheral tissues

Beta phase: gradual decrease in plasma conc. due to drug metabolism and excretion

Question 22

Volume of Distribution

Answer 22

Amount of drug in the body / drug conc. in plasma

Question 23

Drug Metabolism

Answer 23

Enzymatic Modification that normally inactivates drugs and increase water solubility to enhance Secretion by kidneys

Can activate prodrugs to make them active

Mainly liver but also intestines, kidneys, lungs, skin, and blood

Phase I: cytochrome P-450s, do oxidation, hydroxylation, dealkylation, or deamination

Phase II: conjugation with addition of large substituent group like sulfate or glucuronidation, makes more polar

Question 24

Cytochrome P450s

Answer 24

Many kinds, expression is regulated , often membrane bound

Substrates often have high lipid solubility

Use NADPH to reduce substrate

Inhibited by imidazole containing drugs, antibiotics like erythromycin, grapefruit juice, and more

Question 25

Drug Excretion

Answer 25

Uncharged forms of drugs are reabsorbed better in the kidneys Metabolism makes drug metabolites ionized or hydrophilic to improve excretion into urine Increases or decreases in urine pH will impact absorption of weak acids or bases

Question 26

Kinetics of Metabolism

Answer 26

Rate of metabolism: V = vmax [c] / (Km + [c]) First order: when [c] < Km V = vmax/Km * [c] lnC = lnCo - kt t1/2 = ln2 / k or 0.693 / k, is independent of conc. Describes conc. in blood after IV, most common ``` Zero order: when [c] > Km V = vmax/Km C = Co - kt t1/2 = 1/2 * Co / k If elimination becomes saturated ```

Question 27

2 parameters for Pharmacokinetics

Answer 27

Volume of distribution and clearance

Question 28

Clearance

Answer 28

Volume of plasma cleared of drug per unit time (L/hr.) Rate of elimination: CL * [C] t1/2 = 0.693 Vd / CL CL is based on sum of clearance by liver, kidneys, and other excretion pathways

Question 29

Minimum Effective Concentration

Answer 29

Plasma drug conc. below which there is no significant clinical drug response

Question 30

Common Routes of Administration

Answer 30

Sublingual, oral, inhalation, transdermal patch, parenteral like IV, topical, rectal

Question 31

Steady State Conc.

Answer 31

With continued IV infusion or multiple dosing plasma drug conc. reaches a state of eq. when drug intake and elimination are equal About 5 half lives before drug dosing regimen approaches a steady state conc. Proportional to rate of constant infusion, doubling rate of infusion results in doubled steady state conc. but doesn't change the time needed to get there Only t1/2 determines the time to reach the steady state, inhibitors of P450 give shorter time to steady state Inversely proportional to clearance of the drug

Question 32

Factors of Concern for Pharmacokinetics

Answer 32

Health, age, weight, interference by other drugs, genetic variation

Question 33

Genetics risk factors of Diabetes

Answer 33

Autosomal Recessive: CF, chronic pancreatitis, hemochromatosis, pheochromocytoma (tumor in adrenal gland medulla that releases high catecholamines), insulin receptor defects, proinsulin cleavage defect Mitochondrial: MELAS, Kearns Sayre Autosomal Dominant: myotonic dystrophy (3' UTR), maturity onset diabetes of the young (MODY) appears acutely and is polygenic and rare

Question 34

Human Leukocyte Antigen

Answer 34

Strong association with autoimmune disorders 95% of Type I patients have the DR-3 or DR-4 allele, but 1/2 the pop. has either DR-3: antibody against beta cells, later onset DR-4: antibody against insulin, earlier onset Even younger onset of both DR-2: protective Can see antibodies rising and help before get bad symptoms

Question 35

Maturity Onset Diabetes of the Young

Answer 35

Autosomal Dominant, polygenic Hypoinsulinism but more gradual onset compared to type I, LOF or dysfunction of beta cells MODY 2: glucokinase defect, mild glucose intolerance that can be controlled, noted as gestational diabetes often, GOF of this gene leads to congenital hyperinsulinism MODY 1, 3-6: same pathway so similar presentation, delayed secretory response to glucose intake leads to Hyperglycemia over time MODY 5: very uncommon, TCF2 involved in embryonic development of organ systems, associated with pancreatic atrophy, reproductive abnormalities, and renal disease Treatment: sulfonylureas are highly effective and help sensitivity of beta cells to glucose and promote secretion

Question 36

TCF7L2

Answer 36

Transcription factor for proglucagon synthesis Homozygous carriers have 2x increased risk for type II Found in genome wide association study, one of few that works across multiple ethnicities Implicated in colon cancer too

Question 37

Weaknesses of Genome Wide Association Studies

Answer 37

Associations only, not causation Replication is a requirement and need large pop. to find small effect Dependent on data collected that may be inaccurate in older records Only now better applications to non-Europeans

Question 38

Prediabetes Effect on Protein Function

Answer 38

Decrease protein function relative to before due to higher insulin levels LOF, aggregation, cell death, and Type II diabetes results

Question 39

Cadherins

Answer 39

Cell Adhesion Molecules, form junctions Found in epithelial cells, maintains zonula adherens Ca2+ dependent extracellular domain Intracellular domain interacts with cytoplasmic catenins to link cadherins to actin filaments in the cytoplasm Maintain cell-cell interactions Altered in tumor metastasis

Question 40

Integrins

Answer 40

Cell Adhesion Molecules, form junctions Cell-cell and cell-ECM binding Heterodimers, Ca2+ independent extracellular binding domain Signaling in the anchoring junctions, function as mechanosensors and allow signal transduction Adhesion of WBCs to endothelial cell surface Facilitate cell movement in the ECM

Question 41

Zonula Occludens

Answer 41

Tight junctions The most apical junction Prevents paracellular transport between two cells, separate apical domains from lateral/basal domain Composed of occludin and claudin

Question 42

Zonula Adherens

Answer 42

Intermediate junctions Further anchors cells to each other, belt-like appearance Made of actin and E-cadherin-catenin complexes, fuzzy plaques along cytoplasmic side for cadherin-catenin complex and alpha actin/vinculin proteins Ca2+ binds to the cadherin between the cells

Question 43

Macula adherens

Answer 43

Desmosomes, look like spot welds and don't encompass the whole cell, erratic locations below zonula adherens Resist shearing forces, add strength For stratified epithelia like epidermis Composed of desmogleins and desmocolins (Cadherin family molecules) which are bound to cytoplasmic proteins containing desmoplakin and plakoglobin which are bound to keratin in turn

Question 44

Gap Junctions

Answer 44

Allow rapid intercellular communication by allowing direct passage to cytoplasm of the cells Made of connexin that forms a hexamer called connexon, forms an open/close channel between cells to allow transfer of chemicals Coordinate contraction of cardiac muscle, osteocytes excrete waste and get nutrients from bone canaliculi via gap junctions

Question 45

Basement Membrane

Answer 45

Separates the epithelium from connective tissue PAS+, silver reactive: proteoglycans and sugars are capable of reducing silver salts and turning them a deep black Two regions- 1. Basal lamina: penetration indicates tumor metastasis, made of laminins, type IV collagen, proteoglycans, glycoproteins Type VII collagen attaches anchoring fibrils to hemidesmosomes 2. Reticular lamina: made of reticular fibers (type III collagen) and attaches basal lamina to deeper connective tissue

Question 46

Focal Adhesions

Answer 46

Links cytoplasmic actin to basal lamina proteins Integrins are transmembrane proteins that make up focal adhesions, bind fibronectin, collagen, and laminin Help with anchoring and signaling, transmit mechanical changes in STP and used for wound healing Function in cellular movement like wound healing, white blood cell extravasation for inflammation, and tumor cell invasion

Question 47

Hemidesmosomes

Answer 47

Anchor the basal plasma membrane to the basal lamina, found in stratified squamous epithelia Have BP230 and type XVII collagen intracellularly attached to integrins and are attached to lamin 5 and type IV collagen of the basement membrane Type IV collagen is further attached to the connective tissue below via type VII collagen anchoring fibrils

Question 48

Pemphigus Vulgaris

Answer 48

IgG antibodies to desmogleins 1 and 3, leads to shearing of skin and oral mucosa that forms blisters Still attached to basement membrane but lost lateral domain attachment Creates flaccid blisters Nikolsky's sign Immunofluorescence gives a net like pattern Acantholysis is separation of keratinocytes from each other

Question 49

Bullous Pemphigod

Answer 49

IgG antibodies against Type XVII collagen and BP230 of hemidesmosomes Tense blisters that don't rupture easily Epidermis lifted off from dermis, blister is a clear area filled with leukocyte and fibrin No Nikolsky's sign Linear immunofluorescence

Question 50

Dystrophic Epidermolysis Bullosa

Answer 50

Defect in collagen VII that is supposed to anchor fibrils of the connective tissue to the basement membrane Butterfly children Flaccid blisters, epidermis and esophagus Open wounds make prone to infection, chronic blood loss can lead to anemia, and chronic inflammation put at high risk for DNA mutations for squamous cell carcinoma

Question 51

Formation of the Notochord

Answer 51

Occurs during day 17, week 3 Forms by extension from the notochordal process, occurs while primitive streak regresses, forms a hollow tube The notochord process (hollow tube) fuses with endoderm to form the notochordal plate then detached from the endoderm and forms the solid rod of the notochord in the mesoderm space between the endoderm and ectoderm Forms the nucleus pulposus at the center of the vertebral discs in early childhood, gets replaced by mesoderm later

Question 52

Neurulation

Answer 52

Neural plate: thickened ectoderm along midline of the embryo, induced by notochord formation Neural groove: neural plate begin to fold, is the space between the neural folds Neural tube: formed by fusion of the neural folds of the neural groove Neural crest cells: lateral lips of the neural plate detach during the formation of the neural tube, positioned to the side of the neural tube, form components of the PNS Closure of the neural tube begins on day 22 at the middle and progresses in cranial and caudal directions, cranial neuropore closes first in day 25 and then caudal neuropore on day 27

Question 53

Neural Tube Defects

Answer 53

Neurulation fails to occur normally Spina bifida: closed asymptomstic neural tube disorder in which some vertebrae aren't completely closed Anencephaly: open brain and lack of skull vault, occurs due to incomplete fusion of the neural tube in the cranial region

Question 54

Mesoderm Differentiation

Answer 54

Occurs around day 17 Paraxial Mesoderm: near notochord, become somites Lateral plate: opposite side of paraxial mesoderm, will split into 2 layers Intermediate mesoderm: close to notochord and between paraxial mesoderm and lateral plate, become urogenital system

Question 55

Body Folding

Answer 55

Occurs during 4th week Cranial/Caudal Folding: form future head and feet area, forward growth of neural plate causes cranial folding to occur first, yolk sac hangs below stomach area, get regions for the gut and heart Lateral Folding: left and right sides come together and fuse to form a cylinder, the ectoderm covers the entire surface of the embryo except the future umbilicus, gut formed kinda from yolk sac

Question 56

Peak Flow Meters

Answer 56

Portable device that measures the maximum exploratory flow rate Help recognize early changes of worsening pulmonary function Maximum exploratory flow rate is compromised by bronchoconstriction which happens for asthmatics

Question 57

3 Categories of Peak Flow Measurements

Answer 57

Correspond to patient's asthma plan of care Green Zone: 80-100% of the patient's normal peak flow readings, keep up regular meds, asthma is under control Yellow Zone: 50-80% of normal, beginning of the narrowing of the air passages, take rescue inhaler or nebulizer (breathing device that administers meds in mist form for the lungs) to reduce shortness of breath Red Zone: less than 50% of normal, seve4e bronchoconstriction with wheezing and shortness of breath, use rescue inhaler and call doc/go to hospital

Question 58

Drug Metabolism Pharmacogenomics

Answer 58

Genetic polymorphism influence phase I (oxidation, reduction, hydrolysis, and cytochrome P450) and phase II (conjugation) CYP2D6 metabolizes about 20% of drugs but has high genetic variability, CYP3A does the most drug Metabolism at about 40% and has little genetic variability

Question 59

Leading a Cause of death in hospitalized patients

Answer 59

Adverse drug reactions

Question 60

Warfarin

Answer 60

Long term anticoagulation, oral med used for pulmonary embolism, heart valve replacement, and knee/hip replacement Severe bleeding complications in first month for 3% of people, can get Warfarin-Induced skin necrosis Hydroxylated by CYP2C9 Use pharmacogenomics to determine dosing and reducing bleeding complications, use alleles of CYP2C9 and the target enzyme

Question 61

CYP2D6

Answer 61

Metabolize 20% of drugs that include antipsychotics, antidepressants, tamoxifen (a prodrug), and Metoprolol Inhibited by concurrent meds like cocaine and Prozac Has different genetic mutations whose frequency varies by race 4 Metabolizer Groups: Poor, intermediate, efficient (rapid), and ultra rapid metabolizers Vary dose by metabolizer group, PM needs much lower dose than UM Tamoxifen is anti cancer prodrug that gets metabolized by CYP2D6 to active Endoxifen

Question 62

Thiopurine S-methyltransferase | TPMT

Answer 62

Phase II inactivation of thiopurines Thiopurines treat acute lymphocytic leukemia, inflammatory bowel disease, arthritis, transplant immunosuppression 90% of pop. has 2 wildtype copies but small percentage has 2 nonfunctional alleles Low levels of TPMT result in dangerous leukopenia with normal doses of thiopurines

Question 63

Pharmacogenomics Improving Efficacy

Answer 63

Trastuzumab has increased efficacy when treating HER2-positive breast cancer, genetic testing done prior to initiating treatment

Question 64

Pharmacogenomics Testing Clinical Relevance

Answer 64

Avoid adverse drug reactions Improve efficacy of pharmacologic therapy Improve cost effectiveness of pharmacologic therapy: can use quality-adjusted life year or other cost-utility assessments

Question 65

Avoiding Adverse Drug Responses

Answer 65

G6PD-deficient patients have increased risk of hemolytic reactions when taking rasburicase, primaquin, and topical dapsone Genetic Testing is FDA-recommended before treatment Patients with HLA-B*1502 allele have increased risk for Steven-Johnson-Syndrome when taking carbamazepine HLA-B*5701 have increased risk for severe hypersensitivity when taking abacavir for antiviral HIV Thiopurine methyltransferase deficient patients have increased risk of myelotoxicity with azathioprine FDA recommends genetic testing before treatment for all of these

Question 66

Rough vs. Smooth ER

Answer 66

rER: studded with ribosomes, protein synthesis, have cisterna, chief cells of stomach secrete Pepsi oven made from rER sER: lacks ribosomes but structurally similar, have tubules, Leydig cells of the testes make testosterone

Question 67

Smooth ER

Answer 67

Abundant in cells for lipid metabolism and those that secrete/synthesize steroids like adrenal cortical cells and Leydig cells, stained pink (eosinophilic) Forms sarcoplasmic reticulum in skeletal muscle, sequesters Ca2+ and near T-tubules that conduct contractile impulses into the muscle fiber for release Well developed in the liver to detoxify enzymes, cytochrome P450 is anchored in liver sER, metabolize ethanol and barbiturates here

Question 68

Distance from board for visual acuity test

Answer 68

20 ft. From eye chart, should match top number of reading

Question 69

Visual Acuity testing procedure

Answer 69

Keep eye under occluder open and relaxed Make start at middle of chart (line 4 or 5) Need at least 75% accuracy Clean occluder with alcohol and let it dry before test, look at patient Can wear glasses for vision but not readers

Question 70

Pediatric Eye Testing Considerations

Answer 70

Many abnormalities can be treated if found early, should evaluate for strabismus, amblyopia, and refractive errors Infant testing: red reflex and eye alignment/movements, get better at following an object past the midline as grow older, corneal light reflex test, unilateral cover test 3-5: Allen chart has pictures and can use tumbling E chart, can do formal visual acuity testing 5+: HOTV, should use Snellen eye chart for adults if possible since most accurate Standards: 20/40 for 3-4 year olds, 20/20 for school age, problem if two line difference between eyes

Question 71

Geriatric Vision Acuity Considerations

Answer 71

Risk factors- Cataracts: smoking, alcohol, UV exposure, being black Age-related macular degeneration: smoking, family history, and being white Screening test: screening questions not as accurate since dementia, use Snellen chart Doesn't work as well- Amsler grid tests central vision Fundoscopy to see retina damage Treatment- Surgery for cataracts wet age-related macular degeneration: laser photocoagulation, vascular endothelial growth factor Inhibitors Dry ARMD: antioxidants but proof is limited Glaucoma: too much fluid pressure builds up in eye, familial history, can damage ocular nerve and cause blindness Give eye drops, laser surgery, or microscopic glaucoma surgery