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Nursing 3366-600 Pathologic Processes: Implications for Nursing (AP ONLINE COURSE) REQUIRED READING DOCUMENT #1

Instructions: 1. Read this entire RRD (Required Reading Document) and other documents mentioned. 2. Work on Assignment #1 (see Epic site) and submit by designated deadline.

Note about objectives /outcomes and studying for this course: For ALL content in this course, the student will be able to DESCRIBE/DISCUSS/IDENTIFY correlations (links) between pathophysiology of the disease and its clinical manifestations. In other words, #1: how does the pathophysiology of a particular disease cause the signs and symptoms, and #2: if a patient presents the signs and symptoms of a disease, be able to use critical thinking to figure out the disease process that is most likely in that context.

Basic Concepts of Pathophysiology & Implications for Nursing Objectives /outcomes

DESCRIBE/DISCUSS/IDENTIFY: 1. concepts underlying the nomenclature of physiology and pathophysiology. 2. appropriate, general application of those concepts to disease processes and situations.

Outline for Lecture: I. Overview A. Physiology B. Pathophysiology C. Examples II. Some basic physiologic concepts. A. Homeostasis B. Compensation and decompensation III. Pathophysiologic concepts & terminology A. Disease vs disorder vs syndrome

B. Terms relating to elements leading up to a disease C. Terms relating to causes of a disease

D. Terms relating to course of a disease E. Sequela : aftermath of a disease

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I. Overview

A. Physiology-- study of functions & processes that occur in body, mostly the NORMAL processes B. Pathophysiology -- the study of the underlying changes in body physiology that result from disease or injury

C. Examples: 1. physiologic amenorrhea (menstrual flow ceases because of menopause,

pregnancy, etc) versus pathophysiological amenorrhea (menstrual flow ceases because of cancer, for ex.)

2. physiologic albuminuria versus pathophysiological albuminuria

Re: sidebar & other boxed info in all your notes: a. Information in a sidebar box is added knowledge for you, or a review of previous info or sometimes some A&P info, etc b. If the info in the box is prefaced by “FYI,” you won’t be responsible for it on a test. c. If there is no “FYI” preface, the information IS eligible for test material. DO NOT FORGET TO STUDY THESE SIDEBAR NOTES!

FYI: pathology & pathophysiology come from Latin root word “pathos”—suffering.)

Some standard language usage clarifications: o “AKA” means “also known as.” o “IE” or “ie” means “in other

words.” o “eg” means “for example.” o this sign before a word means

“approximately:” ~

Read page xxi in your book, along with the following notes.

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II. Some basic physiologic concepts.

A. Homeostasis—maintenance of constant conditions in the body’s internal environment 1. Cells must have constant supply of nutrients, H2O, O2, and exist in narrow pH & temperature range 2. Maintaining homeostasis is essentially a balancing act-- the body is always trying to “right itself” when homeostasis is challenged by changes. 3. These challenges to the body’s balance are sometimes called stressors.

B. Compensation and decompensation 1. The return to homeostasis after being challenged by a stressor is called compensation; similar words are adaptation, healing, etc.

a. Compensation is achieved by the body’s use of control mechanisms, also called compensatory mechanisms.

b. Control / compensatory mechanisms examples: 1) Example of compensatory response to “normal” daily-life

stressors: if you run out of available glucose between meals & can’t eat immediately, your body turns to the “back-up” system of glycogenolysis —breakdown of glycogen, which is a form of stored glucose.

2) Example of compensatory response to pathologic stressors: if you’ve lost a lot of blood (massive bleeding) or water (dehydration), the body uses certain compensatory techniques to keep remaining fluid volume circulating as effectively as possible (temporary measures until the cause of the problem gets fixed) :

a) heart rate would increase to get blood around faster to temporarily make up for loss of volume.

b) also, arteries in your periphery (arms and legs) would constrict, shunting whatever blood volume is left to the central areas, that is, to your most important organs—brain, heart, lungs, kidneys.

2. If the body is unable to appropriately meet the challenge of stressors-- for example, if the control mechanisms are “exhausted”-- compensation can deteriorate either rapidly or slowly into decompensation— the failure to compensate, adapt, heal, etc.

Other examples of compensatory mechanisms: o If there is too much CO2 in your body for some reason, control mechanisms in the respiratory centers of the brain increase

respiratory rate so that CO2 exhalation is increased. o If you have too much blood volume or the pressure in your arteries is too high over a long period of time: 1) the heart will need to pump with more force to eject blood into your arteries. 2) to do this, it will have to “shore up” its muscle-- this is called muscle hypertrophy: the heart muscle compensates for the extra stressors by undergoing hypertrophy. o Checks and balances example: 1) part of the inflammatory response to a cut on the toe is to begin the clotting process 2) if the clotting process continued indefinitely, the whole body would be one big clot 3) so, the fibrinolytic system that dismantles a clot is the “check and balance” to the clotting process 4) summary: control mechanism to bleeding = clotting; “check” to the clotting = fibrinolytic system.

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III. Pathophysiologic concepts & terminology A. Disease vs disorder vs syndrome

1. a disease is a harmful condition of the body (and/or mind); a disorder is a disturbance in the healthiness of the body; a syndrome is a collection of symptoms

2. for this class these terms will be basically interchangeable, as they all are a disturbance in body homeostasis; most of the time I will use the term disease (or abbreviate as “dz.”)

B. Terms relating to elements leading up to a disease 1. risk factors

a. factors that or contribute to and/or increase probability that a dz will occur …”setting the stage”

b. ex-- heredity, age, ethnicity, lifestyle (smoking, eating habits, etc), environment

2. precipitating factor a. a condition or event that triggers a pathologic event or disorder ….

the “kick-off” b. ex—“an asthma attack can be precipitated by exertion”

C. Terms relating to causes of a disease 1. etiology-- the cause of a disease; includes all factors that contribute to development of dz; examples: a. etiology of AIDS: HIV (human immunodeficiency virus) b. etiology of rheumatic heart disease: autoimmune reaction c. TB (tuberculosis): mycobacterium 3. idiopathic—dz with unidentifiable cause 4. iatrogenic problem -- occurs as result of medical treatment

ex—if kidney failure is due to improper use of antibiotics prescribed by a healthcare provider you could say “the etiology of the kidney failure was iatrogenic.”

5. nosocomial problems—result as consequence of being in hospital environment

ex— urinary tract infection is called a nosocomial infection if it developed while patient was in the hospital.

D. Terms relating to course of a disease 1. Clinical manifestations (ie, S&S)-- the demonstration of the presence of a

sign and/or symptom of a disease a. signs-- manifestations that can be objectively identified by a trained

observer b. symptoms -- subjective manifestations that can only be reported by

the person experiencing them-- pain, nausea, fatigue (***note, most often on a patient chart, “signs and symptoms” appear as “S & S” or S/S; also, often in medical vernacular, “symptoms” is used as a shortcut instead of saying “signs and symptoms.”)

c. local versus systemic S&S: 1) some S&S are local: redness, swelling, heat, rash, &

lymphadenopathy in a particular area 2) others are systemic, such as fever, urticaria (hives), malaise (“I

feel dragged out” or “awful all over”), systemic lymphadenopathy

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d. acuity and timing of S&S 1) acute S&S:

a) fairly rapid appearance of S&S of dz (over a day to several days); usually last only a short time

ex: “The patient had an acute URI (upper respiratory infection) that resolved within a few days.”

b) also can mean increase in severity

ex: “The acuity of the patient’s URI increased and he had to be hospitalized.”

2) chronic S&S —develop more slowly; S&S are often insidious and last longer and/or wax and wane over months or years.

a) remissions—periods when S&S disappear or diminish significantly (wane)

b) exacerbations—periods when S&S become worse or more severe (wax); exacerbate—to provoke, to make worse.

ex: “The patient had an exacerbation of his chronic asthma and had to go to the hospital.”

e. terms relating to location of manifestations: 1) central a) usually refers to problem, situation, etc, that is occurring towards the center, or “core,” of the body b) often used when referring to essential organ systems

like brain, heart, lungs, kidneys;

ex— when someone loses a lot of blood, the body shunts most of the remaining blood away from non-essential areas such as gut, hands, feet, so that the essential organs are oxygenated—ie, most of the volume of blood ends up circulating centrally.

c) the more central an area or problem is, the more proximal to the core it is;

ex—“the arm was fractured proximal to the elbow.”

this means a break between elbow & shoulder 2) peripheral, or periphery a) refers to problem, situation, etc, that is occurring

towards the outer parts of the body, away from core i. ex—if we lose a lot of blood, the blood vessels of

the periphery often constrict so that not a lot of blood can circulate into those areas (mainly arms & legs)

ii. thus there is more blood going to central areas such as the heart, brain, lungs, and kidneys—blood has been shunted to those areas

iii. this is why sometimes a sign of shock is cool, pale extremities.

Basic definition of “shock:” low BP plus S&S of not getting enough blood to different parts of the body (ex—confusion from not getting blood to brain).

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b) the more peripheral an area or problem is, or further away from the core of the body, the more distal it is

ex—“distal to the blood clot in the left coronary artery, the tissue lost oxygenation & died.”

2. Prognosis-- the predicted outcome of a dz based on certain factors: a. the usual course of that particular dz

b. individual’s characteristics; ex: 1) age: patients at either end of age spectrum --infants & the

elderly are at higher risk for a poor prognosis due to immature or “worn out” immune systems, respectively.

2) presence of comorbidities– two or more coexisting medical conditions; this increases chance of poor prognosis

ex—“The patient’s comorbidities of heart disease and lung disease contributed to his poor prognosis in recovering from pneumonia.”

D. _sequela (plural: sequelae): aftermath of a disease 1. a sequela is any abnormal condition that follows and is the result of disease, injury, or treatment; synonym = complications 2. occasionally the term is used as simply “outcome,” such as: “A positive

sequela of getting pneumonia was that the patient stopped smoking;” but most of time “sequela” is used with a negative connotation.

3. severity of sequela varies; examples of sequelae with various degrees of seriousness: a. sequela of rheumatic fever can sometimes be a bad heart valve. b. possible sequela of chicken pox scarring

c. possible sequela of stroke weakness on one side of the body

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Here is a partial list of terms to look over to make sure you understand them (other terms may come up that you will

need to look up as well). Many should be familiar from A&P. YOU WON’T BE SPECIFICALLY TESTED ON THESE, but they will help you parse out word meanings.

a/an – prefix meaning not, without ab- prefix meaning from, away from, off ad- prefix meaning increase, adherence, to or toward

aer- prefix meaning the air, or gas algia- suffix referring to pain or painful condition ascend- to move upward to a higher position asymmetrical –denoting a lack of symmetry between two or more parts that are alike bi- prefix meaning twice or double bilateral- relating to or having two sides blast- denotes an immature precursor cell brady- prefix meaning slow dorsal- pertaining to the back dys- prefix referring to “bad” or difficulty ectomy- suffix denoting removal of an anatomical part emia- suffix meaning “in the blood” hemo- prefix referring to blood hemorrhage- escape of blood from the intravascular space. To bleed. hyper- prefix meaning excessive, above normal

hypo-prefix deficient, below normal ICU- IntensiveCare Unit “i” – suffix that often creates plural form; ex—one embolus, two emboli. iasis—suffix meaning state or condition. idio- prefix meaning private, distinctive, or peculiar to.

6 inferior- situated below or directly downward itis – suffix meaning having to do with inflammation or infection

IV- intravenous lipo – pertaining to fat lytic- suffix creates adjective form of lysis lysis- suffix refers to destruction of a substances, usually a cell macro- prefix meaning large, long megaly- suffix meaning large micro- prefix denoting smallness necro-prefix meaning death ostomy- suffix meaning artificial opening (stoma) into the urinary or gastrointestinal tract or trachea ology- suffix meaning the study of a subject osis—suffix meaning condition otomy- suffix meaning a cutting operation plasty- suffix referring to molding, shaping or the result there of a surgical procedure. scopy- suffix referring to viewing or seeing superior- situated above or directly upward

symmetrical- equality in two like parts tachy- prefix meaning rapid unilateral- confined to one side of the body only ventral – pertaining to the front side (as opposed to dorsal) VS—vital signs:

o BP—blood pressure (measured as systolic over diastolic mm of Hg) o HR—heart rate (measured in beats per minute). o RR—respiratory rate (breaths per minute) o T or temp—temperature. o SO2 or pulse oximeter or pulse ox or O2 sat—oxygen saturation (measured as percentage—we will go into this

more in a later lecture)

************************************ ALSO, VERY IMPORTANT!! FOR EACH SET OF READINGS, MAKE YOUR OWN VOCABULARY LIST FOR YOUR OWN STUDY BENEFIT. For this set of readings only, I made a list to give you an example. (In any set of readings, if there are words that I have not explained, and that you do not know, look them up in your book or a medical dictionary and/or ask me about them. You will be responsible for all vocabulary. NOTE: vocabulary of basic concepts will be used throughout the semester in other readings and on tests, so BE SURE to get familiar with them.

physiologic pathologic homeostasis compensation decompensation etiology risk factors prognosis comorbidity sequela

acute / acuity chronic

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Genetic Influence in Disease

Objectives /outcomes

DESCRIBE/DISCUSS/IDENTIFY:

various multifactorial genetic disorders pathophysiology of basic chromosomal problems such as Down’s syndrome & the Philadelphia

chromosome

single-gene alterations resulting in protein synthesis defects and their relationship to disease processes & symptoms, such as sickle cell anemia, polycystic kidney disease, &, hemophilia

some therapeutic uses of recombinant DNA.

remission exacerbation central peripheral proximal distal etiology precipitating factor idiopathic

iatrogenic nosocomial

See last couple of pages of “How-Manual” in RESOURCES of your Epic home site if you

would like to know how to do a “flashcard

concept map.” The emphasis in doing flashcards this new way is to realize that

knowing a word and its definition (rote memorization) is not enough—you must

understand its CONTEXT. That’s what gives

it true meaning & application potential.

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NOTE: Here between the wavy lines is a little A&P background (a very brief review about what you should already have learned in A&P [see also ch 2 in book]… this first part won’t be on a test… just a foundation for patho info)

1. Gene definition and function a. Definition of a gene--a segment of a DNA molecule that is composed of an ordered sequence of nucleotide bases (adenine, guanine, cytosine, thymine) b. Main functions of genes: coding for synthesis of proteins that form our traits and functional characteristics. 1) Examples of these include “permanent” proteins such as eye pigment, hair color, and blood type in a developing fetus, as well as more subtle inherited traits like outgoing personality or susceptibility to certain diseases. 2) There are also “day-to-day” functional proteins such as hormones, antigens, antibodies, enzymes, etc. c. When there is a mutation of a gene, the protein it is responsible for often malfunctions. 1) You can have a pretty good idea of what type of disorder & S&S occur when you understand this pathologic process.

2) Ex—if the gene that codes for lactase becomes mutated, lactase cannot properly breakdown and process lactose. Lactose ingestion then causes diarrhea. This is called lactose intolerance.

2. Packaging of genes: chromosomes a. The DNA helix containing genes goes through many shapes during the cell life but at one point takes the shape that we are most familiar with– the rod-shaped body in the nucleus of cells called a chromosome. 1) To summarize: a sequence of nucleotide bases forms a gene; genes make up a DNA molecule, and that DNA molecule forms into a specialized shape called a chromosome 2) A chromosome can be thought of (very simplistically) as a string of multi- purpose beads, with the beads being genes. b. A person receives 23 chromosomes from each parent, so you end up with 23 pairs, or a total of 46. 1) 22 pairs are autosomal– ie, NOT sex chromosomes– and each pair is closely alike. 2) The other pair is the sex chromosomes– XX or XY. 3) For purposes of study they can be arranged in a karyotype (a picture) ex— chromosome #1 from mom is matched up with chromosome #1 from dad.

c. Autosomal chromosome pairs (#1-22). 1) For these pairs, each has genes that closely match “partners” on the other chromosome. 2) Partner genes have the same location (“locus”) on each respective chromosome, code for the same trait, and are called “a pair of alleles.” 3) A pair of alleles are almost exactly alike except that one can be dominant & one can be recessive (or they can both be dominant or both be recessive). 4) We notate recessive genes with a lower-case letter & a dominant gene as an upper-case letter.

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a) The combinations are called genotypes & represent what was inherited from mom & dad.

b) Examples of various combinations (randomly using the letter “g”), can be GG (homozygous dominant); gg (homozygous recessive); Gg

(heterozygous). d. There is one pair of sex chromosomes (#23) which work very differently. There is

info on them & on sex-linked disorders later in these notes, but you won’t be tested on that info.

e. If a geneticist is trying to figure out the percent chance of two people with certain genotypes having a child with certain genetic characteristics, a Punnett square is often used. (Note: you must understand & be able to do Punnett squares for the exam).

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Outline for Reading & Studying Genetic Influence in Disease: A. Overview 1. definition of genetic disorders

2. categorizing genetic disorders 3. mitochondrial DNA disorders 4. multifactorial 5. chromosomal 6. single-gene

B. Single-gene disorders 1. overview/ categories: autosomal recessive, autosomal dominant, sex-linked 2. autosomal recessive a. overview

b. example of autosomal recessive disorder--sickle cell anemia 3. autosomal dominant a. overview b. example of autosomal dominant disorder—polycystic kidney disease 4. sex-linked—example is hemophilia C. Recombinant DNA– a form of genetic engineering

A. Overview 1. broad definition of “genetic disorders”-- a disease caused by abnormalities in an individual’s genetic material

2. there are several ways of categorizing genetic disorders: a. inherited vs “spontaneous”

1) example of inherited disorders—sickle cell disease is caused by an inherited, altered (AKA, “mutated”) gene (see below)

2) example of spontaneous—high level of exposure to radiation causes a

mutation in a gene becomes an “oncogene” which causes rapid, wild proliferation of cell growth skin cancer develops.

b. other ways to categorize include using the following four groupings: disorders of mitochondrial DNA, multifactorial, chromosomal, single-gene.

3. mitochondrial DNA disorders a. majority of DNA is found in nucleus of cells but small bits of DNA are also

found in mitochondria b. disorders of this DNA are very uncommon & won’t be discussed here

4. multifactorial genetic disorders -- combination of environmental triggers and variations / mutations of genes, plus sometimes inherited tendencies; examples:

Some explanations of terms: “Environmental” is used here to mean any influence other than inherited. “Onco” prefix means “cancer-related”

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a. various cancers such as lung cancer: begins by smoke & toxins irritating bronchial tissue one or more genes in cells of that tissue begin to be deranged—oncogenes created code for wild, uncontrolled growth of cells.

b. many common diseases such as hypertension (HTN), coronary artery disease (CAD) & diabetes mellitus (DM) are now known to be caused or highly influenced by a mix of environmental and inherited components.

c. teratogenic disorders: 1) a teratogen is any influence — eg, drugs, radiation, viruses-- that can

cause congenital defects 2) congenital defects are abnormalities that are either detectable at birth

and/or can be attributed to fetal development “glitches.”

3) so “teratogenic disorders” and “congenital defects” are virtually interchangeable terms

4) specific examples: a) fetal alcohol syndrome (FAS) occurs because toxicity of alcohol

causes gene mutations during gestational development. b) “thalidomide babies” – born with abnormal arms and legs due

to mothers taking the drug thalidomide for nausea during early pregnancy.

5. chromosomal disorders (AKA, chromosomal aberrations) a. definition-- a type of genetic disorder that results from alterations to the

numbers or structure of a chromosome, which in turn alters the “local” genes (genes in the immediate area)--the genes’ functionality is disrupted and they don’t code proteins correctly, giving rise to the phenotype (S&S) of the disorder.

b. alteration to NUMBERS of chromosomes is called an aneuploidy. 1) aneuploidies have the suffix “somy;” for instance, a generic term for

“more than usual numbers of chromosomes” would be polysomy-- Down’s syndrome is an example of a polysomy

2) Down’s is a disorder of abnormal numbers of chromosomes that is sometimes associated with pregnancies of women >35 years old.

3) it is a “glitch” that occurs in very early cellular division and chromosomal distribution of a fertilized egg: instead of ending up with the normal number--46 chromosomes-- the fetus ends up with 47

4) the extra chromosome occurs at site #21 -- the 21st chromosome set has three chromosomes instead of two. a) thus the other name for this type of Down’s is trisomy 21. b) phenotype of trisomy 21 includes mental retardation and typical

physical characteristics such as low-set ears, epicanthic fold to the eyes, short limbs, and a larger-than-normal tongue.

c. example of alterations to STRUCTURE of chromosomes—Philadelphia chromosome 1) some types of chromosomal aberrations are caused by alterations in

chromosomal structure, such as deletion, duplication, or rearrangement of gene sites (translocation) on the chromosome

2) an example of this is the Philadelphia chromosome, which results from translocation & will be discussed further in another set of readings.

FYI: chromosomal disorders occur in ~1% of

live births (2% for women older than 35 years) & are leading known cause of

mental retardation & miscarriage--about 50% of

all recovered first-semester spontaneous abortions

(miscarriages) have major chromosome abnormalities that would have made

them not viable.

Putting things together: One of the subcategories of chromosomal disorders is aneuploidy. Trisomy 21 (Down’s) is a polysomic aneuploidy. Did you understand that?

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6. single-gene disorders – discussed below….

B. Single-gene disorders 1. overview

a. single-gene disorders are usually due to an inherited mutated gene b. since genes code for proteins, when a gene mutates so that its protein product can no longer carry out its normal function, a disorder can result. c. single-gene disorders are inherited in recognizable patterns: autosomal recessive, autosomal dominant, and sex-linked.

2. autosomal recessive disorder a. overview 1) an autosomal recessive disorder occurs when a mutated (“diseased”), recessive (“weak”) gene partners up with an allele that is also recessive & diseased; those alleles are notated with two lower-case letters. 2) the protein that they code for will then malfunction & an abnormality/ disease/ disorder will occur that relates to that “bad” protein

b. example of autosomal recessive disorder--sickle cell anemia 1) genotype and patho development a) at a certain locus on a certain pair of chromosomes, a pair of alleles has the job of coding for the creation of normally shaped hemoglobin (Hgb) b) but if during fertilization a person inherits a sickle-cell disease

gene from mom – ie, a recessive, mutated Hgb-coding gene – and ALSO inherits a sickle-cell disease gene from dad:

(1) this person would have a homozygous genotype of the recessive sickle cell genes: ss

(2) those abnormal recessive alleles will code for abnormally-shaped Hgb (sickle-shaped), which will make the RBCs sickle-shaped (there are ~300 Hgb molecules per RBC, so enough sickled Hgbs in an RBC will deform the RBC too)

(3) because these RBCs do not have the usual round & smooth shape, they are more easily damaged as they go through the blood stream; ultimately this results in less-than-normal numbers of RBCs—this is the definition of anemia.

2) phenotype—a person who has an ss genotype will HAVE the disease sickle cell anemia—ie, their phenotype is having the S&S caused by the above genotype and patho development:

KEY to drawings: = mutated gene

= normal gene

FYI: other examples: phenylketonuria (PKU), cystic fibrosis, Tay-Sachs disease, Wilson’s disease, and many more.

s s

FYI: there are more than 6,000 known single-gene disorders, which occur in about 1 out of every 200 births.

Remember: When assigning notations for autosomal recessive diseases, the “big” letter will be the

dominant, normal, non-diseased allele, and the “little” letter will be the diseased allele.

The suffix “emia” means “in the blood.” Anemia literally means “no blood,” but in actuality it is used to mean “there are less-than-normal numbers of RBCs in the blood.”

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a) SOB (shortness of breath), weakness & fatigue due to decreased O2 being carried to tissues of the body; this decreased carrying capacity is because of: (1) anemia: less numbers of RBCs to carry the Hgb which in

turn carries the O2 (2) deformed Hgb simply cannot carry the usual numbers of

O2 molecules b) ischemic pain, especially in the joints; patho of this type of pain:

(1) the deformed RBCs “clog” up the capillaries that usually carry O2-rich blood to the tissues

(2) this results in distal tissues that are starved to O2 & “cry out” in pain.

3) other combinations of alleles a) if during fertilization a person inherits a sickle-cell disease gene from one parent but a normal Hgb-coding gene from the other parent, the person’s genotype for Hgb would be: _Ss_

b) we call this a “heterozygous genotype for sickle cell anemia” & we know that because the NORMAL gene is dominant over the sickle-cell recessive gene, the person will NOT have the disease but they may pass on the gene to offspring. (1) this is called being a carrier; so Ss is a sickle cell carrier. (2) rarely, a carrier will have a milder phenotype of the disease—ie, mild S&S; this situation is called “having the trait.” (Someone with sickle cell trait has the genotype Ss but has mild S&S of sickle cell disease.)

c) someone with the genotype SS doesn’t have to worry about either having the disease or passing it on—they are what is called “homozygous normal.”

3. autosomal dominant disorders a. overview 1) occurs when a person inherits a mutated, diseased gene that is dominant

2) ie, the gene that codes for a certain disease characteristic is dominant, and the gene that codes for the normal characteristic is recessive (exactly opposite of autosomal recessive)

b. example of autosomal dominant disorder—polycystic kidney disease (PKD)

1) genotype & patho development a) at a certain locus on a certain pair of chromosomes, a pair of alleles has the job of coding for the creation of normal kidney tissue b) if during fertilization a person inherits a kidney tissue gene that has a mutation, that gene will “want” to code for abnormal kidneys. c) in a dominant disease such as PKD, the mutated gene is the strong one, so even if it is paired with a normal allele, it will override the normal allele’s coding.

When assigning notations

for autosomal dominant diseases, the “big” letter will

be the dominant, diseased

allele, and the “little” letter will be the normal, non-

diseased allele.

If cells are not getting enough oxygen and it is due to a circulatory malfunction, the problem is called ischemia. Pain in the tissue that is not getting enough oxygen is called ischemic pain.

FYI: other examples: Huntington’s disease neurofibromatosis, Marfan’s syndrome

(see Punnett square pg 48)

(see Punnett square pg 51)

(WHEN YOU ARE STUDYING MATERIAL IN THIS COURSE, BE SURE TO KNOW HOW TO LINK S&S TO THE PATHO OF THE DISEASE & VICE VERSA; this section is good example of being able to do that.)

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d) in PKD, this results in the kidney tissue developing cysts, which can reduces various kidney functions and lead to kidney failure as a person goes through life.

2) genotype notation a) if we use the letter “P” to designate PKD, the genotype for someone that HAS the disease would look like this: PP or Pp. b) only a person with a genotype of pp

(homozygous recessive) would NOT have the disease

3) S&S

a) hematuria (blood in urine), proteinuria, frequent kidney infections

b) pain at costovertebral angles and abdomen c) kidney stones

4. sex-linked disorders a. normal physiology of sex chromosomes:

1) The two X’s in a woman work just like autosomal chromosomes – a gene on one X has a partner allele at the same locus on the other X that usually code for the same trait.

2) But in a male the genes on his X have no comparable partner allele on his Y.

3) We notate these as such: Xl Xl (homozygous female); XL Xl (heterozygous female); Xl Y or XL Y for the male.

b. types of sex-linked disorders: 1) possibilities include X-linked dominant, X-linked recessive, & Y-linked. 2) X-linked dominant and any kind of Y-linked diseases are rare—sex- linked diseases most commonly fall under X-linked recessive 3) therefore “X-linked” and “sex-linked” terminologies are often interchanged, and when someone says “sex-linked,” they often mean “X-linked recessive.” c. X-linked recessive diseases are caused by a recessive allele that is always located only on an X chromosome 1) in most cases, a female who has the diseased recessive gene on one of her X chromosomes is protected by a normal dominant gene on her other X chromosome, so a female will rarely have an X-linked disease—she will only be a carrier 2) but a male who gets an X chromosome with the diseased gene will not have a matching normal gene on another X chromosome, because he only has a Y chromosome 3) therefore, the phenotype of most X-linked disorders is usually expressed in male offspring. c. example of sex-linked disorder—hemophilia 1) there are several types of hemophilia, each caused by different gene mutations on the X chromosome. 2) normally the genes code for one of the coagulation factors that facilitates normal clotting when there is an injury; examples—Factor XIII & Factor IX. 3) if one of these genes mutates, it may code for a defective

coagulation factor, resulting in altered ability to clot.

When assigning notations for X-linked recessive diseases, use XX for women & XY for men. Then attach letters to the X’s. The “big” letter will be dominant, normal, non-diseased allele, and the “little” letter will be the

diseased allele.

FYI: Other examples include certain types of muscular dystrophy.

see if you can draw & label all 3 possible allele pairing combinations for this autosomal dominant disorder; I will start you with just plain circles and you can fill in “P” or “p”…. Then think: will this

person HAVE the disease or not?

or or

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4) because the hemophilia gene is an X-linked gene, the genotype for someone that has the disease would look like this: Xh Y; genotypes of Xh XH, XH XH, or XH Y would not have the disease

C. Recombinant DNA– a form of genetic engineering 1. many alterations in DNA came about as a natural part of evolution, but now we can deliberately alter DNA in the interests of medicine and science.

2. recombinant DNA is a “new” DNA that results from purposefully combining two or more different sources of DNA; ex-- altering (“engineering”) DNA codons in bacteria

to make proteins the bacteria would not ordinarily produce

3. current applications of this process: a. human growth hormone for children lacking it. b. exogenous (“from outside the body”) insulin for diabetics. c. factor VIII for hemophiliacs.

d. drugs like tPA & tenecteplase—given as “clot-buster” in patients having MI (an MI, a myocardial infarction is when a clot develops in a coronary artery & blocks blood flow to the distal tissue, which begins to die… thus if a drug can get rid of the clot, flow will be restored & tissue will be saved.)

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Intracellular Functions and Disorders

Objectives /outcomes

DESCRIBE/DISCUSS/IDENTIFY: 1. normal cellular metabolism and its alternate states, including anaerobic metabolism and the processes of

glycogenesis, glycogenolysis, and gluconeogenesis.

2. the effect of alterations of key molecular substances such as sodium, potassium, and calcium on electrical properties of cells.

3. the relationship of all the above to certain disease processes and signs and symptoms (S&S), including: hypoxic states

alterations of glucose availability.

alterations in usage of certain vitamins.

hyperpolarized and hypopolarized plasma membranes.

4. basic states of acidosis and alkalosis & how the body compensates.

Outline for Intracellular Functions and Disorders I. Overview

A. Alterations in cellular-level function B. Etiology of these disruptions

II. Hypoxia’s effect on cellular-level function A. Overview of hypoxia B. Sequelae of hypoxia

III. Effect of nutritional alterations on cellular-level function. A. Overview B. A review of NORMAL glucose use and back-up systems

(see Punnett square pg 54)

***In each category of autosomal dominant, autosomal recessive, and sex-linked disorders, be sure you are able to figure out the percent chance of two people with certain genotypes having children with varying genotypes & possible phenotypes – do this with Punnett squares.

IMPORTANT NOTE: As you come across various numbers in your reading, be aware that very few of them will need to be memorized. Exceptions include numbers that I feel will be very useful to know in your nursing practice. Those numbers I will indicate with wordage such as “know now and forever.” That means they may come up again at any time in the semester and you will STILL need to know them. Please feel free to ask me about this issue and any other.

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C. Examples of disease processes related to cellular metabolism “back-up plans” D. Examples of other disorders that can contribute to disruption in metabolic pathway

IV. Alterations in solute status A. A&P overview of select solutes

B. A&P overview of normal electrical function of cells C. A&P overview of body fluid compartments

D. Cellular electrical problems secondary to alterations in electrolyte balance E. Acid / base sequelae of solute imbalance, ie, acid / base imbalance ~~~~~~~~~~~~

I. Overview

A. Alterations in cellular-level function 1. Many normal daily changes in body homeostasis can affect the metabolic

pathway (upon which we depend for energy in the form of ATP), and usually the body can adjust & maintain equilibrium—sort of an ongoing “fine-tuning.”

2. But there are also problems that more seriously disrupt homeostasis of cellular metabolism and the provision of ATP for body needs; it is more difficult for the body to adjust & return to equilibrium in these cases.

3. Many of the disorders & disease processes that we will study in this course either CAUSE or are CAUSED BY some sort of cellular-level disruption that eventually leads to decrease in ATP.

B. Etiology of these disruptions include: 1. hypoxia —decrease in amount of oxygen to cell or ability to use oxygen

appropriately (part II) 2. nutritional problems such as decreased glucose & vitamin availability for cell

use (part III) 3. changes in balance of electrolytes & other solutes, including acid/base imbalance (part IV) 4 changes in fluid distribution (this will be discussed in RRD 4).

II. Hypoxia (decrease in oxygen)—effect on cellular-level function

A. Overview of hypoxia: has a spectrum of etiology and seriousness: from simply overworked muscles in extreme exercise (the muscles use up immediate available oxygen), to someone who is having difficulty breathing & therefore cannot get enough oxygen to the heart to circulate it to the tissues, to someone whose artery in the arm is cut, so the tissues distal to the trauma cannot get oxygen, and so on. B. Sequelae of hypoxia (see page 2 of concept map) 1. if there is hypoxia: a. cellular metabolism has to “recycle” through glycolysis rather than continue down the usual aerobic pathway

This is A&P review info & won’t be tested as such. However, understanding it is CRUCIAL

to understanding the patho.

FYI: All of above imbalances rarely “stand alone”—usually one abnormality triggers another; ex: a bacteria causes disturbance in permeability of lung cells’ plasma membrane there is pathological influx of water into

cells causes swelling in organelles such as mitochondria interrupts electron transport chain functioning no

ATPs to fuel energy needs of lung cells breathing is compromised hypoxia (diminished O2 to cells) reliance

on glycolysis lactic acidosis further disturbance in function of lung cells & other cells of body (body’s cells

“hate” acidosis!) etc.

Again, please review and understand the concept map “THE METABOLIC PATHWAY & DISTURBANCES.”

.

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b. this is because glycolysis is the only step that can operate under normal, aerobic conditions, AND can also operate under anaerobic conditions 2. positive side to anaerobic glycolysis: a. it can give 2 molecules of ATP per molecule of glucose to give energy to the cell. b. thus, it is a temporary stop-gap measure that keeps your body going until the cells can get more O2 so that aerobic metabolism can be re- established. 3. negative side to anaerobic glycolysis: a. 2 molecule of ATP is not enough to keep going for a long time. b. also, every time the metabolic process must “recycle” through glycolysis, multiple molecules of pyruvate (pyruvic acid) accumulate, resulting in acidosis.

4. summary: two main sequela result from hypoxia:

a. deficiency of ATP for cellular functions; ex—without ATP, the Na / K pump of each cell cannot maintain normal electrical cell membrane status and propagation of electrical impulses will be disrupted.

b. altered acid/ base balance, especially acidosis; significance: acidosis from something like hypoxia or reliance on gluconeogenesis (more on this in next section) can dangerously tip body pH out of its narrow, desirable range fairly quickly

5. all the above can cause damage and death to tissues (more on “altered tissue” in another RRD).

III. Effect of nutritional alterations on cellular-level function. A. Overview

1. cells have certain nutritional needs to carry on normal metabolic function a. glucose is obtained from carbohydrates to begin the cellular metabolic pathway that leads to energy provision in the form of ATPs

b. vitamins (and other substances) provide the “support staff” for the metabolic pathway.

2. process of glucose access & usage depends on cellular metabolic needs at any given moment.

B. A review of NORMAL glucose use and back-up systems: 1. if you have just eaten, glucose in the blood normally goes up, a state of

temporary hyperglycemia; this triggers the pancreas to secrete insulin to circulate to cells and assist in getting glucose molecules from the blood into the cells to use as the main source of cellular energy.

2. if intake of food / glucose is greater than immediate cellular energy needs, insulin directs the excess glucose to be stored as glycogen_ in the liver. This is called _glycogenesis (genesis = “creation of”).

refer to concept map

acidosis—a state of greater-than-usual concentration of acidic substances in the blood and cells.

Aerobic– O2 is present (this is the ideal,

“normal” situation). Anaerobic– low or absent O2.

The processes above are considered to be “regulatory:” insulin triggers regulatory, “building up” processes of 1) glucose entering cells, & 2) the creation of glycogen (glycogenesis).

Key physiologic principle: The byproducts of the body’s normal metabolic activities are slightly more acidic than alkaline. To counteract that acidic tendency, the body “likes” to keep a very narrow and slightly alkaline pH range of the blood—

7.35 to 7.45 (Know this range “now & forever.”)

Glycogen is a large molecule that is too big to be used for energy as it is, but when necessary it can be stimulated to break down into small glucose molecules that can be used more effectively. Think of it as “stored glucose.”

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3. later, if you don’t eat and / or the availability of glucose is less than cellular energy needs, a state of _hypoglycemia (low blood sugar)usually exists. a. certain hormones called the counterregulatory hormones are triggered by low blood glucose: 1) epinephrine from the adrenal medulla 2) cortisol from the adrenal cortex 3) growth hormone (GH) from the pituitary 4) glucagon from the pancreas.

b. roles of these hormones include: 1) “alarms”—sensations of hunger, shakiness, sweating, irritability —these are telling you to “EAT!” 2) if you don’t eat, the body takes the first step in its “back-up plan:” the counterregulatory hormones stimulate the conversion of glycogen to glucose. a) this process is called glycogenolysis (lysis = “breakdown”) &

results in a higher blood sugar, correcting the hypoglycemia & making glucose available to the cells for energy use.

b) many times a day if our body needs some glucose & we cannot immediately take it orally, glycogenolysis takes place as a “stop gap measure” till we can take in glucose.

c. the next step in body’s normal “back-up plan” 1) if glucose is either unavailable or cannot get into the cell to participate in the metabolic pathway, and glycogenolysis has already exhausted a person’s store of glycogen, the body breaks down fats and protein.

2) this is called gluconeogenesis--the use of any other substance besides carbohydrates for cellular energy; this means breaking down fats and proteins for energy.

3) one of the breakdown products of fats and proteins is ketones a) “good” characteristic of ketones: they can offer the body some

energy—usually enough to be a “stop gap” till glucose is available.

b) two “bad” characteristics of ketones: (1) they are acids-- over time there is a danger of acidosis (2) they can’t be used by brain cells—brain cells MUST have

glucose for energy.

C. Examples of disease processes related to cellular metabolism “back-up plans”

1. glycogen storage diseases -- abnormalities in glycogenesis or glycogenolysis a. ex-- McArdle’s disease—an autosomal recessive disease in which which normal ability to breakdown glycogen (glycogenolysis) is diminished.

BACK UP PLAN #1:

Glycogenolysis

BACK UP PLAN

#2:

Gluconeogenesis

AKA, stress hormones because hypoglycemia is stressful for the body, so

they come “to the rescue.”.

Summary: Glycogenolysis & gluconeogenesis are considered to be “breaking-down,” “counterregulatory” processes triggered by the counterregulatory hormones when hypoglycemia is present.

***If you’ve ever felt dizzy, dull-witted or cognitively challenged when hypoglycemic, it’s because your brain cells are ESPECIALLY reliant on glucose for energy. If brain cells are deprived of glucose, they can become electrically disturbed and a person can become unconscious, have a seizure, and / or even die. Clinical significance: Often when a patient presents with an altered level of consciousness, one of the first things we do is test the blood sugar.

FYI: 3 main ketones:

a) acetoacetic acid b) beta-hydroxybutyric acid c) acetone (another acid)

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b. S&S that might occur in a person with this kind of disease-- muscle weakness & cramps during exercise because of no energy reserves.

2. Type I diabetes: gluconeogenesis taken to extreme: (gluconeogenesis is normal body back-up process, but if disease process alters it or causes sustained usage, then has potentially detrimental consequences)

a. people with Type I diabetes mellitus do not make insulin without insulin, glucose unable to get into cells, glycogen is eventually used up, (so BACK-UP PLAN #1 is used up), and body turns to sustained gluconeogenesis (BACK-UP PLAN #2) as its main energy pathway. b. this is ok for awhile, but eventually sustained gluconeogenesis causes ketone over-accumulation, resulting in hyperketonemia (high levels of ketones in the blood)

c. hyperketonemia is manifested by: 1) blood test showing high serum ketones. 2) AND usually the following as well: a) blood test showing LOW (<7.35) blood pH—this would be called ketoacidosis—a form of acidosis; and/or b) urine test which shows ketonuria (ketones spill into urine); and/or

c) S&S such as acetone breath (excretion via lungs). D. Examples of other disorders / problems that can contribute to disruption in metabolic pathway: 1. alterations in vitamin & mineral access or usage a. overview

1) glucose begins the metabolic pathway, but certain other molecules such as vitamins & minerals are necessary to maximize the creation of ATP—they are nutrients of which we need only small amounts but which are crucial to our bodies’ well-being [as can be seen in concept map, page 2…niacin (B3), thiamine (B1), riboflavin (B2); iron (Fe).]

2) in most cases sufficient amounts cannot be made by our bodies and must be supplied by diet.

3) in underdeveloped countries, vitamin deficiencies are often due to complete lack of availability of certain foods; in U.S., vitamin deficiencies occur usually as a result of poor dietary habits or chronic disease

b. example of a type of patient that nurses often see who would be high risk for vitamin deficiencies: an alcoholic. 1) often an alcoholic has very poor diet—obtains minimal iron and B

vitamins such as thiamine (as well as countless other deficiencies) 2) as a sequela of iron deficiency, may develop iron-deficiency anemia;

seeing iron’s role in the metabolic pathway, what kinds of S&S do you think might this patient have? (S&S related to low ATP & low oxygenation—weakness, fatigue SOB),

3) thiamine deficiency is called beriberi & sequelae include neuro problems:

FYI: Of course, a diabetic would also have high serum glucose (no insulin = no ability to move glucose from bloodstream into cells = hyperglycemia) and glucosuria (glucose spilling into urine), but right now we are just discussing hyperketonemia —the “downside” of sustained gluconeogenesis.

FYI—dietary iron can be obtained in liver, salmon, beans, eggs; thiamine is in lean meats, fish, milk. Also many of our grocery products are fortified with these & other vitamins & minerals.

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a) because B1 is particularly important in the functioning of neurologic cells (including brain tissue), many S&S of depletion of this vitamin (& other B vitamins) show up as neurologic problems

b) examples of neurologic issues associated with thiamine deficiency: (1) Wernicke-Korsakoff syndrome – classically associated

with alcoholism and manifested as memory loss and ataxia (staggering, uncoordinated gait)

(2) paresthesia--numbness & tingling or other unusual sensations, usually in legs (this is seen in B12 deficiency too).

2. various drugs, both medicinal & street drugs. 3. poisons; ex—cyanide

a. cyanide present in insecticides, rodenticides, metal polishes, burning wool & silk, certain drugs such as nitroprusside; now considered potential bioterrorism drug. b. S&S of toxicity include headache, agitation, confusion, vomiting, eventually respiratory problems & death. c. mechanism of action-- inhibits cytochrome oxidase (look on concept map)

IV. Alterations in solute status A. A&P overview of select solutes (solute are molecules that have been dissolved in a fluid—in this case in the fluid of the

blood, which is mostly water) 1. proteins a. found: 1) in the plasma; examples: albumin and lipoproteins. 2) in the cells—proteins are abundant intracellular anions b. a few of their most important functions are: 1) helping with electrical balance across cell membrane. . 2) helping with fluid compartment balance; this is especially true of albumin, which is the most abundant protein in the plasma. 3) serving in many other roles such as immunoglobulins (antibodies) and as coagulation factors such as prothrombin, thrombin, etc 3. glucose—common solute in the blood & cells; important for energy, but also can cause fluid shifts.

4. electrolytes (electrolytes are molecules that, once in fluid, separate into charged atoms called ions) a sodium-- Na+: 1) the most abundant cation in extracellular fluids 2) the key electrolyte that drives water movement—generally speaking, “where Na+ goes, H2O follows” 3) most often travels in the blood as sodium chloride—NaCl

b chloride--Cl-: also tends to “follow” Na—they easily form a bond and usually travel

together in the bloodstream as NaCl until they get to cells, where they dissociate in order to go in and out of cell membrane ion channels.

c. potassium-- K+: the main cation in the intracellular fluid; one of most important functions is to balance Na+ 1) the kidneys use Na & K to offset each other in the process of maintaining homeostasis a) ex--if there is not enough Na and / or water in the body, aldosterone is secreted by the adrenal gland--this stimulates the kidneys to “hold on” to Na and excrete K b) the opposite happens if we need to “hold on” to K or if we need to get rid of Na. 2) also, the Na / K pump keep Na & K in the ratios needed to drive appropriate cell membrane electrical impulse propagation

paresthesia--“pins & needles”

feeling (like when your foot falls asleep & “wakes up”)

FYI—when I make long lists like this, it is not always important to memorize the

items specifically… most of them time it is a certain concept that I want you to

“get”… if you have questions about what to know for a test in a “listing”

case like this, just ask.

***Before getting into the alterations in solute status, carefully look over the following info (sections A, B, & C, between the dotted lines below)—this is A&P stuff, not tested per se, but you still must have a good grasp of it to understand the patho material.***

CLARIFICATION: Beriberi is the disease name of general thiamine deficiency. Wernicke-Korsakoff syndrome is a group of neurologic S&S especially seen in alcoholics with beriberi.

19 a) Na/K “pumps” are part of cell membranes and pump out 3 Na ions for every 2 K ions that come into cell—ie, because more cations are being pumped out than

are staying inside, the inside of the cell is slightly negative with respect to the outside. b) this is what keeps the cell membrane slightly & confers a resting membrane potential (RMP) of ~ -90mV to most cell membranes d. calcium-- Ca+: 1) a cation that has many important uses in the body, including: a) Ca+ is an important part of muscle cell contraction; ex-- (1) it affects the normal entrance of Na into the cells (2) effect on Na+ is an inverse one: --less calcium in the body more Na will go into cell. --more calcium less Na will go into cell b) Ca+ is one of the factors needed to clot blood properly c) also has great importance in bone growth & maintenance. 2) regulated by activation of vitamin D, by PTH (parathyroid hormone), and by the kidneys. e. phosphorous-- usually exists as phosphate-- PO4- : 1) the main intracellular anion 2) balances Ca+ --generally, when one is high, the other is low. f. important ions / molecules in acid/base balance:

1) the “acid gang:” hydrogen—H+ & carbon dioxide-- CO2 2) the “alkali guy:” bicarbonate--HCO3-.

B. A&P overview of normal electrical function of cells – again, carefully look over the info in this box

during your pre-lecture notes review as well info in Prep #2—we will go over this “normal electrical function” material only briefly in class, and you MUST understand it in order to understand the patho

1) normal resting membrane potential (RMP) of most cells is about -90mv; it is negative because in the resting

state of a cell there are slightly more anions than cations inside the cell membrane. 2) normal depolarization point (point at which cell contracts) for most cells is about +30mv 3) consider these numbers as a “normal” polar status

4) think of the term “polar” as two points that are “apart”— one point is the RMP of -90 and one point is the “goal” of the cell—to reach +30, the point at which it can contract

This represents a single cell of the tissues. K+, Na+ are cations (I randomly put 5 of them inside the cell). The anions inside the cell are represented by DASHES and there are six of them.

+ 30 mV (normal depolarization point—the contraction point-- the cell can now contract-- “go to work”)

This is the blood flowing in capillaries throughout tissue. It has a certain number-- “normal” – of electrolyte levels (ie, normal balance of cations & anions).

K+ K+ K+ Na+ Na+

- - - - - -

-90mv (normal RMP…the resting state of the cell)

Normal balance of tissue cell cations & anions …note

that there are normally more anions than cations inside the cell, giving the RMP its normal negative charge.

5) When an electrical signal reaches the resting cell, it changes the balance of cations & anions in the cell— more cations flood the cell. This increases the positivity of the cell membrane until it reaches ~ +30 mV. This is the “goal charge” for cell membranes to achieve in order to depolarize (contract).

Normal “POLAR GAP STATUS”..

The dotted line arrow stands for the distance from the RMP (one pole)

to its “goal charge” of +30mV (the other

pole). It must reach this charge of +30 so

that the cell can depolarize (contract)—“go to work”. When

there is a normal RMP of around -90mV, there is

a “normal” distance to +30mV – ie, a “normal” polar gap.

This lightning bolt represents an electrical signal coming from a nerve or previous cell that increases flow of cations into “our” representative cell, thus changing the membrane charge from -90mV to +30mV.

-90mv

(normal RMP)

K+ K+ K+ Na+ Na+

_ _ _ _ _

Cations like Na+ flood into cell & begin changing 90mV to a more positive charge; ie, -90 starts becoming more positive

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C. A&P of body fluid compartments [NOTE: basically “fluid” translates to “water”]

1. 2 basic fluid compartments—extracellular & intracellular

a. intracellular fluid compartment is the fluid-filled space inside cells (solutes are dissolved in the fluid) b. extracellular compartment has 2 components: 1) the interstitial fluid compartment—fluid-filled space between cells and blood vessels (solutes are dissolved in the fluid) 2) the plasma fluid compartment

a) this is the fluid-filled space between the walls of blood vessels; we tend to talk about this compartment as THE BLOOD

b) however, there are several other commonly used terms for the plasma compartment, besides “the blood,” which YOU MUST UNDERSTAND: the main ones are vasculature, bloodstream, “in the vascular system,” “in the blood vessels,” “in the circulatory system,” “blood volume,” plasma, blood, circulation

2. Solute movement and fluid shifts: a. as explained above, there are 3 fluid compartments; however in the clinical setting, we tend to think in

terms of the compartments most relevant to us, to how we view our patients. b. for instance, though cells & interstitial spaces are separate compartments, we often lump them

together and call it “TISSUE.” Example: If the blood is diluted with extra water, fluid moves from the plasma space to the interstitial space & eventually into the cells. But often a short cut is used in talking about this phenomenon: I will often say “fluid moves from the blood to the tissue.”

c. so whether talking about solute diffusion or fluid shifts, think in terms of two compartments involved in the “action:” BLOOD (“B” for short in the notes) and TISSUE (“T”).

d. THE PATHO OF FLUID SHIFTS WILL BE DISCUSSE MORE IN RR #2.

D. Cellular electrical problems secondary to alterations in electrolyte balance 1. overview

a. before discussing specific pathologic electrical changes in cells, let’s look at how electrolyte balance in the body compartments gets “altered” in the first place to result in electrical pathologies:

1) homeostasis, or balance, of solutes in the body means there are approximately the same sum of ions & other solutes inside each fluid

compartment compared to the compartment “next door.” 2) so if there is an alteration in the solution composition in one

compartment, a domino effect begins—diffusion of the solute particles results in changes in the next compartment, then the next, etc. (This occurs because the body is always striving to return to a normal, even, homeostatic composition of solutes in each compartment.)

3) as a general rule (and for simplicity purposes in this class) ALWAYS think of these changes in solute & fluid balance as occurring first in the plasma compartment (ie, blood, “B”), then spreading to the tissue (interstitial fluid & cells-- “T”).

4) the changes / imbalances exist until the body can “right” itself or in some cases, get medical intervention as needed.

b. specific example of “domino effect” of solute shifts from compartment to compartment (this is a therapeutic example, not a pathologic one, but the

same fundamental principle applies to any situation): 1) if a person is taking potassium (K+) pills, the pills are digested and

then absorbed into the blood vessels in the lining of the stomach and duodenum

2) then the K+ enters into the blood stream and increases the K+ level there—in a sense, this creates an electrolyte imbalance, since now there is more K+ in one compartment (the blood) than usual.

Remember that solute molecules usually follow the property of diffusion—they want to go to a compartment where there are LESS particles.

Here’s what I mean by the change occurring FIRST in the blood compartment…

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3) as the blood (with its now more-than-normal-number of K+) circulates to various tissues, the K+ will eventually diffuse INTO the tissue, because initially the tissue held a LESSER number of K+ than the changed blood.

c. for simplicity sake, we will discuss only cation movement between blood and tissue; the particular cations & related terminology are:

a. potassium (K+); higher-than-normal numbers of K in blood is called hyperkalemia; lower-than-normal numbers of K in blood is called

hypokalemia. b. sodium (Na+); high Na+ = hypernatremia; low = hyponatremia. c. calcium (Ca+); high Ca+ = hypercalcemia; low = hypocalcemia.

2. how electrolyte imbalances change electrical status of cells a. as noted in the A&P section (pg 7 of these notes) “normal” electrical status

exists when there is a normal distance-- ie normal “polar gap status”-- between the two poles of: #1-- the RMP of ~90mV (when a cell is “resting” between each of its

contractions, the charge on its membrane is -90mV). #2-- the “goal” charge of +30mV (the charge usually needed in order for a

cell to contract to “go to work,” do its “job;” that job depends on what kind of cell it is—cardiomyocyte, deltoid muscle cell, eyelid muscle cell, brain cells, etc)

b. if, however, a disorder/disease/situation disrupts the normal balance of electrolytes in the blood, eventually the balance of cations & anions in the tissue cells will be affected

1) this causes a resetting of the cells’ resting membrane potential (RMP)

to a more positive number or a less positive number

3. HYPOPOLARIZED states: situations in which membranes of cells have been reset to

a MORE positive number than normal, shortening the polar gap status & making them more sensitive

a. examples of states in which cells become hypopolarized: hyperkalemia, hypernatremia, hypocalcemia

b. mechanisms of action: 1) hyperkalemia & hypernatremia are easy to understand: more cations

in the blood mean that eventually more cations will diffuse from blood into cells

a) within the cell, this creates a more “positive” state, ie, increased positivity since more cations have moved in

b) so instead of the usual RMP of -90mV, the cell membrane is RESET to more positive RMP

2) if the RMP is reset to a MORE positive number than normal, it will shorten the polar status —this is called hypopolarization

3) if the RMP is reset to a LESS positive number than normal, it will lengthen the polar status—this is called hyperpolarization

SEE

PODCAST –

it will help you visualize

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c) for instance it might increase its positivity to -60 mV; the polar gap has shortened now (-60 is closer to +30mV than -90 was) and we say the cell is HYPOpolarized.

d) now, when stimulated by an incoming electrical signal, there is less distance for the cells’ charge to get to the depolarization point (ie, to contract)

e) the cell is now much more sensitive than normal and will “go to work” (contract) quicker.

2) hypocalcemia is a little harder to understand: a) the very presence of low calcium levels in the blood as the

blood circulates in tissue beds triggers an INCREASE in permeability of cell membranes to Na+ so that MORE Na+ is allowed INTO the cell than normal

b) so now the situation is exactly like any other in which there are

more cations entering the cell increased cations in cell = increased positivity (decreased negativity)= _hypopolarization.

c. S&S of hypopolarization: 1) pathologic hypopolarization of cells manifests clinically as muscles that

are too sensitive – ie, hyperactive, “irritable” 2) they contract with smaller-than-normal stimulation, often resulting in

muscle tics or spasms (example—positive Chvostek’s sign)

3) if the spasms are severe and/or unrelenting, this is called tetany.

4. HYPERPOLARIZED states: situations in which membranes of cells have been reset to a LESS positive number than normal, lengthening the polar gap status & making them less sensitive

a. examples of states in which cells become hyperpolarized: hypokalemia, hyponatremia, hypercalcemia

b. mechanisms of action: 1) hypokalemia & hyponatremia are easy to understand: less cations in

the blood mean that eventually more cations will diffuse out of the cells into the blood

a) within the cell, this creates a LESS “positive” state, ie, decreased positivity, since more cations have moved out.

b) so instead of the usual RMP of -90mV, the cell membrane is RESET to less positive RMP

c) for instance it might decrease its positivity to -120 mV; the polar gap has lengthened now (-60 is further from +30mV than -90 was) and we say the cell is HYPERpolarized.

d) now, when stimulated by an incoming electrical signal, there is more distance for the cells’ charge to get to the depolarization point (ie, to contract)

**** increased positivity = hypopolarization (shortened polar gap) = hyperactivity of cells****

So remember: hypocalcemia has the peculiar property of causing more Na+ to go INTO cells, so that

cells have abnormally MORE cations inside them hypopolarized.

http://www.youtube.com/watch?v=cQ-xMeNAqys-- example of Chvostek’s: When the cheek is touched, the cells of

the muscles and nerves in the area HYPERreact, are HYPERsensitive, due to the HYPOpolarization from problems such as hyperkalemia, hypernatremia, and especially HYPOcalcemia. The cheek involuntarily contracts.

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e) the cell is now much less sensitive than normal and it will take longer for it to “go to work” (contract).

2) hypercalcemia (like hypocalcemia) is a little harder to understand: a) the very presence of high calcium levels in the blood as the

blood circulates in tissue beds triggers an DECREASE in permeability of cell membranes to Na+ so that LESS Na+ is allowed INTO the cell than normal

b) so now the situation is exactly like any other in which there are more cations LEAVING the cell decreased cations in cell = decreased positivity = hyperpolarization.

c. S&S of hyperpolarization: 1) pathologic hyperpolarization of cells manifests clinically as muscles that

are less sensitive than usual– ie, hypoactive. 2) they contract more slowly, often resulting in patients complaining of

fatigue, lethargy, mental slowness.

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

IMPORTANT INFO ABOUT ABGS: o “ABGs” stands for arterial blood gases—a measurement of oxygenation & acid/base balance in the blood. o Some of the measurements are indeed actually “gases”—PCO2, PO2 in particular. But for now we will be concentrating on

metabolic issues that focus on two measurements that aren’t gases: pH & HCO3 --pH is a measurement of “how acidic is this person?” The LOWER the pH, the more acidic the person’s blood is. The HGHER the pH, the more alkali the person’s blood is. The acidity of someone’s blood reflects in general how acidic the rest of the body is—other fluids, cells, etc.

-- HCO3 is the chemical name for bicarbonate.

Here are some principles to remember (see also, ABGs chart):

o For our purposes in this class, think of CO2 & H+ as the main members of the “ACID GANG” and HCO3 as the “ALKALI GUY.” --Too much CO2 or H+ in the blood = too much acid gang = acidosis. Too little CO2 or H+= alkalosis. --Too much HCO3 in the blood – too much alkali guy = alkalosis. Too little HCO3= acidosis.

o Also, think of the lungs controlling or “ruling” CO2; they have little control of HCO3. Think of the kidneys as controlling or “ruling” HCO3 & H+. (These principles are somewhat simplistic, but they are a good start for learning how to interpret ABGS.)

**** decreased positivity = hyperpolarization (lengthened polar gap) = hypoactivity of cells****

Summary: When given a solute-change situation, this is what should go on in your mind: 1. I have been given a scenario in which there is a change in solute composition of the body and must figure out how

that affects cellular electrical status. 2. The first thing I must do is figure out what has happened in the blood—are there now MORE solutes or LESS in the

blood now? 3.. Based on the change above, and the process of diffusion: When the blood circulates to the tissue, will solutes go

from blood to tissue or tissue to blood? 4. Let’s assume the solutes are cations …. If diffusion takes them from B to T: they will be making cells more

electrically positive than normal …If diffusion takes them from T to B, then the cells will become LESS positive.

Going further: when trying to figure out whether a cell has become hypopolarized or hyperpolarized, ask yourself: 1. As a result of a disorder & resultant diffusion, are there now MORE cations than usual in the cell or LESS than

usual? 2. More cations have moved into cell = RMP is more positive than usual= shorter distance to +30 = hypopolarized = more sensitive to stimulation = “hyperactive” S&S (muscle spasms, positive Chvostek’s sign, possible tetany, etc) OR…. 3. More cations have moved OUT of cell= RMP is less positive than usual= longer distance to +30 = hyperpolarized =

less sensitive to stimulation = “hypoactive” S&S (fatigue, lethargy, mental slowness).

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E. Acid / base sequelae of solute imbalance, ie, acid / base imbalance 1. acidosis

a. overview 1) most often clinically measured as part of ABGs—arterial blood gases; acidosis exists when the blood pH is < 7.35. 2) as noted before, body needs narrow range of slightly alkaline to counteract an overall tendency of metabolic activities towards acidosis, which is a state not well tolerated by the body. 3) acidosis can cause variety of S&S, including: a) headache, disorientation b) nausea, vomiting c) muscle pain, cramps. d) shortness of breath e) low blood pressure (BP), shock f) organ failure, death. 4) types of acidosis are based generally on what caused the acidosis: the two types are metabolic and respiratory

b. metabolic acidosis (think of the word metabolic in the ABGs context as

meaning that the acid/ base imbalance is related to a problem in the

kidneys and/or any other disorder/body system EXCEPT the lungs (respiratory system).

1) caused by a metabolic problem that results in one or more of the following: a) excess accumulation of H+ (and other acids) in the body b) not enough excretion of H+ in the urine. c) not enough HCO3 being made. d) too much HCO3 being excreted in the urine. 2) any of the above can create a state of _LOW pH and low HCO3

3) an example of a metabolic acidosis etiology a) available O2 in a muscle is used up from exercising too hard: hypoxia in those tissues results in reliance on anaerobic glycolysis for energy needs. b) as a result, the pyruvate (AKA pyruvic acid) molecules that are created during glycolysis do not undergo normal processing via the Kreb’s cycle and instead are converted to another type of acid called lactic acid (lactic acid is full of H+ ions) c) lactic acid can be a friend for awhile—it can be converted to glucose in the liver for emergency energy needs—but if acid levels get too high either locally or systemically, they become “irritating” to the tissues and /or organ systems. 4) other examples of processes that may result in metabolic acidosis: a) kidney failure: because sick kidneys can’t excrete H+ or

make HCO3 acid accumulation acidosis. b) diabetic ketoacidosis: ketones have accumulated because body

is in sustained gluconeogenesis_

Heavy acid gang (say, too much H+) overwhelms alkali guy—this makes HCO3 “light”—ie, have a LOW number. When the acid gang takes over like this, the pH becomes low.

balance

acid gang is heavy, making pH low

alkali guy is light because the acid gang has “chased him out of town”

(Don’t memorize–

is just listed for perspective

on how damaging

acidosis can be.)

***Do memorize and remember, “now and

forever,” normal pH range for the body:

7.35 to 7.45.

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c) poisons, drug overdose, alcohol: breakdown products are acidotic

5) compensation for metabolic acidosis (the body’s attempt to return to normal acid/base balance):

a) the primary means of compensating for metabolic acidosis is via the lungs. b) the lungs try to decrease the acid gang in the body by increasing the amount of CO2 that is exhaled c) they do this by increasing the rate & / or depth of respirations. d) end result is that the pH is increased back to normal.

c. respiratory acidosis 1) state of low pH caused by a ventilation problem such as diminished effectiveness of breathing or decreased respiratory rate (more on this in pulmonary lecture). 2) this results in retention of CO2 (accumulation of an acid)acidosis

3) compensation is by the kidneys: HCO3 production by the kidneys will be increased to buffer the situation, ie, to counteract the acid (CO2) that has accumulated from poor ventilation.

2. alkalosis: a. overview 1) clinically considered alkalosis when blood pH is > 7.45 2) alkalosis is a much less common abnormality than acidosis, though both can be very serious. 3) types of alkalosis: metabolic and respiratory, depending on cause

b) metabolic alkalosis 1) etiology-- a metabolic problem that results in one or more of the following: a) excess accumulation of HCO3 in the body b) not enough excretion of HCO3 in the urine. c) too much acid (H+ and others) being excreted in the urine or lost in other metabolic ways. d) not enough acid being made

Compensation (“fixing”): --The lungs or the kidneys are the means of compensation to restore normal acid/base balance. --If the original problem is metabolic, the lungs will “fix” (by controlling CO2 as a gas). Think like this: If the kidneys are “sick” (as manifested by metabolic acidosis or alkalosis), they can’t do the fixing—the lungs must do the fixing. --If the original problem is respiratory, the kidneys will fix in various ways. Think like this: If the lungs are “sick” (as manifested by respiratory acidosis or alkalosis), they can’t do the fixing—the kidneys must do the fixing. --To figure out HOW they will fix the problem, ask yourself, “what needs to happen to get back to normal pH?” --Also, BE CAREFUL to clearly separate PROBLEM from COMPENSATION. When given a scenario, for example, FIRST figure out what the PROBLEM is—metabolic vs respiratory acidosis or alkalosis. THEN figure out the COMPENSATORY response. ******************** NOTE: when we talk about compensation in this context, we are referring to the BODY’s attempt to return things to homeostasis. In the medical setting, however, we provide more immediate and different means to correct the problems. Many of you who are in the medical field already may trip yourself up on a test by thinking about how we can jump in and help the patient with a drug or

intervention. ALL questions will be based on how the BODY compensates on its own.

heavy alkali guy outweighs light acid gang, making the pH high

alkali guy heavy

acid gang

light, pH high

Please note that there is a difference between talking about CO2 (an acid in the body) and PCO2 (partial pressure of CO2 as a gas). But, FOR THIS SET OF READINGS AND THIS TEST, DON’T WORRY ABOUT PCO2 IN THE ABGS FOR NOW. We will come back to it in the pulmonary section. But DO think of CO2 (without the “P” in front) as an acid. Anytime it accumulates, it will cause acidosis. If it accumulates as a result of a metabolic problem, it will drive down the pH and the HCO3. If it accumulates as a result of a respiratory problem, it will still drive down the pH but not affect the HCO3).

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2) any of the above can create a state of high pH and high HCO3 3) some causes of metabolic alkalosis: a) large amount of vomiting. b) over-ingestion of bicarbonate (HCO3). 4) compensation is via lungs, by decreasing rate & depth of respirations. c. respiratory alkalosis 1) state of high pH caused by hyperventilation—increased rate of breathing results in “blowing off” more CO2— less CO2 in the blood = LESS ACID GANG = higher pH. (more on this in pulmonary lecture).

2) example of a cause of respiratory alkalosis: _anxiety (when someone is anxious, they begin to hyperventilate)_.

3) compensation is via kidneys, by _decreasing amount of HCO3 made or increasing its excretion.

3. summary of acid /base imbalances: a. respiratory acidosis: the cause is some sort of respiratory problem in

which not enough CO2 is exhaled CO2 is retained & causes the pH to drop to < 7.35. b. metabolic acidosis: the cause is some sort of metabolic problem usually related to anaerobic metabolism and /or the kidneys not being able to get rid of H+ or to make HCO3 (such as in renal failure)—this causes the pH to drop to < 7.35. c. respiratory alkalosis: the cause is some sort of respiratory problem in which too much CO2 is exhaled and causes the pH to go up to > 7.45. d. metabolic alkalosis: the cause is some sort of metabolic problem usually related to too much HCO3 ingestion, sick kidneys not getting rid of HCO3, or vomiting too much acid—this cause the pH to go up to > 7.45.

e. re: compensating for an acid/base imbalance: the kidneys compensate for an imbalance caused by a respiratory problem; the lungs compensate for an imbalance caused by a metabolic problem (remember, “metabolic” includes kidneys).

For test 1, concentrate mostly on metabolic ABGs alterations as reflected in pH & HCO3; there might be an answer choice for respiratory acidosis or alkalosis, but look at the HCO3 and if it has changed out of the norm, you know the imbalance is metabolic. In test 3 material, we will encompass all this info, adding PO2 & PCO2 then.