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1

Contents of the apical domain of epithelial cells

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

2

Microvilli

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

3

Stereocilia

Long, immotile microvilli

Hair cells of inner ear, epididymis, and vas deferens

Serve as mechanoreceptors

Made of actin

4

Motile cilia

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

5

Kartagener Syndrome

Primary Ciliary Dyskinesia

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

6

Primary cilia

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

7

Autosomal Dominant Polycystic Kidney Disease

Mutations for the polycstin genes of primary cilia

Enlarged cystic kidneys and can get cysts elsewhere like in pancreas

8

GLP-1

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

9

GIP

Glucose-dependent Insulinotropic Peptide

Secreted by K cells in jejunum

Secretion not decreased in type II but resistant

Similar effects to GLP-1

Not a therapeutic target

10

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

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

11

Counterregulatory Hormones

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

12

Impaired defense against hypoglycemia in type I

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

13

Diabetic Ketoacidosis

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

14

Clinical symptoms of diabetic ketoacidosis

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

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

15

Pharmacokinetics

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

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

16

4 Factors affecting pharmacokinetics

Absorption

Distribution

Metabolism

Excretion

17

Drug Absorption

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

18

Bioavailability

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

19

Factors for Bioavailability

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

20

Drug Distribution blood flow

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

21

Two compartment model of drug distribution in plasma after IV

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

22

Volume of Distribution

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

23

Drug Metabolism

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

24

Cytochrome P450s

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

25

Drug Excretion

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

26

Kinetics of Metabolism

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

27

2 parameters for Pharmacokinetics

Volume of distribution and clearance

28

Clearance

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

29

Minimum Effective Concentration

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

30

Common Routes of Administration

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

31

Steady State Conc.

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

32

Factors of Concern for Pharmacokinetics

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

33

Genetics risk factors of Diabetes

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

34

Human Leukocyte Antigen

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

35

Maturity Onset Diabetes of the Young

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

36

TCF7L2

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

37

Weaknesses of Genome Wide Association Studies

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

38

Prediabetes Effect on Protein Function

Decrease protein function relative to before due to higher insulin levels

LOF, aggregation, cell death, and Type II diabetes results

39

Cadherins

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

40

Integrins

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

41

Zonula Occludens

Tight junctions

The most apical junction

Prevents paracellular transport between two cells, separate apical domains from lateral/basal domain

Composed of occludin and claudin

42

Zonula Adherens

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

43

Macula adherens

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

44

Gap Junctions

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

45

Basement Membrane

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

46

Focal Adhesions

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

47

Hemidesmosomes

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

48

Pemphigus Vulgaris

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

49

Bullous Pemphigod

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

50

Dystrophic Epidermolysis Bullosa

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

51

Formation of the Notochord

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

52

Neurulation

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

53

Neural Tube Defects

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

54

Mesoderm Differentiation

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

55

Body Folding

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

56

Peak Flow Meters

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

57

3 Categories of Peak Flow Measurements

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

58

Drug Metabolism Pharmacogenomics

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

59

Leading a Cause of death in hospitalized patients

Adverse drug reactions

60

Warfarin

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

61

CYP2D6

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

62

Thiopurine S-methyltransferase
(TPMT)

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

63

Pharmacogenomics Improving Efficacy

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

64

Pharmacogenomics Testing Clinical Relevance

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

65

Avoiding Adverse Drug Responses

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

66

Rough vs. Smooth ER

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

67

Smooth ER

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

68

Distance from board for visual acuity test

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

69

Visual Acuity testing procedure

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

70

Pediatric Eye Testing Considerations

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

71

Geriatric Vision Acuity Considerations

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