8/31/17 Flashcards
Contents of the apical domain of epithelial cells
Enzymes Receptors Ion channels Carrier proteins Special structures: microvilli, sterocilia, motile cilia, nonmotile cilia
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
Stereocilia
Long, immotile microvilli
Hair cells of inner ear, epididymis, and vas deferens
Serve as mechanoreceptors
Made of actin
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
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
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
Autosomal Dominant Polycystic Kidney Disease
Mutations for the polycstin genes of primary cilia
Enlarged cystic kidneys and can get cysts elsewhere like in pancreas
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
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
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
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
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
Diabetic Ketoacidosis
Need-
1. Insulin deficiency: leads to increased FA delivery to liver and subsequent movement into mitochondria
- 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
Clinical symptoms of diabetic ketoacidosis
Nausea, vomiting, thirsty, abdominal pain, shortness of breath
Tachycardia, dehydration, hypotension, respiratory distress, lethargy, possible coma
Pharmacokinetics
Time-dependent changes of drug conc. in body following drug administration
Looks at conc. in plasma, target tissues, etc.
4 Factors affecting pharmacokinetics
Absorption
Distribution
Metabolism
Excretion
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
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
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
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
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
Volume of Distribution
Amount of drug in the body / drug conc. in plasma
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
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
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
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
2 parameters for Pharmacokinetics
Volume of distribution and clearance
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
Minimum Effective Concentration
Plasma drug conc. below which there is no significant clinical drug response
Common Routes of Administration
Sublingual, oral, inhalation, transdermal patch, parenteral like IV, topical, rectal
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
Factors of Concern for Pharmacokinetics
Health, age, weight, interference by other drugs, genetic variation
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
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
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
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
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
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
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
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
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
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
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
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
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
- Reticular lamina: made of reticular fibers (type III collagen) and attaches basal lamina to deeper connective tissue
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
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
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
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
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
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
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
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
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
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
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
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
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
Leading a Cause of death in hospitalized patients
Adverse drug reactions
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
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
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
Pharmacogenomics Improving Efficacy
Trastuzumab has increased efficacy when treating HER2-positive breast cancer, genetic testing done prior to initiating treatment
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
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
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
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
Distance from board for visual acuity test
20 ft. From eye chart, should match top number of reading
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
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
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
