General Pathology (genetics & developmental diseases / prematurity, fluid & hemodynamic disorders) Flashcards
lecture 8 (prematurity, fluid and hemodynamics disorders)
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prematurity
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how long normal pregnancy last
Normal pregnancy lasts 40 weeks (9.2 months)
what is avergae fetus weight
Fetus attains viability and average weight of 3500g (7 lbs 12 oz)
7.7 pounds
3500g
what is prematurity
children born before 37th week and less than 2500 g
(5.5 pounds)
“Low birthweight is when a baby is born weighing less than 5 pounds, 8 ounces”
“Some babies with low birthweight are healthy, even though they’re small. But having a low weight at birth can cause serious health problems for some babies.”
immaturity
(infant immaturity)
less than 1500g; cannot survive outside neonatal intensive care units
1500g
(3.3 pounds)
neonatal intensive care unit
“Newborn babies who need intensive medical care are often put in a special area of the hospital called the neonatal intensive care unit (NICU)”
neonatal meaning
Neonatal refers to the first 28 days of life.
spontaneous aboriton / miscarriage
Approximately 5-10% of pregnancies terminate prematurely
why “ ??
Maternal factors
Fetal factors
Placental factors
when does maturation of fetal lungs occur (which portion of pregnancy?)
last 3 months of pregnancy
what happens during this time (that fetal lungs mature) ?
lungs expand and principle components of alveoli are formed
what do avleolar cells secrete?
Alveolar cells begin secreting surfactant
Keeps alveoli open
surfactant define
a substance which tends to reduce the surface tension of a liquid in which it is dissolved.
surfactant in lungs
Surfactant is a mixture of fat and proteins made in the lungs. Surfactant coats the alveoli (the air sacs in the lungs where oxygen enters the body).
This prevents the alveoli from sticking together when your baby exhales.
“Pulmonary surfactant is essential for life as it lines the alveoli to lower surface tension, thereby preventing atelectasis during breathing.”
atelectasis
partial or complete collapse of the lung.
ateles = imperfect
ektasis = extension
Neonatal Respiratory Distress Syndrome (NRDS)
If fetus born prematurely, functionally immature lungs cannot sustain normal respiration
—> (NO SURFACTANT (?) not enough (?))
Alveoli collapse
Oxygen cannot diffuse into circulation
Cells damaged and die
Neonatal Respiratory Distress Syndrome (NRDS)
AND NECROSIS
Necrotic cells and proteins coagulate and form HYALINE MEMBRANES
Gas exchange impeded
Infant can die of anoxia within 48 hours
Anoxia most prominently affects brain
HYALINE MEMBRANES
When there is not enough surfactant, the tiny alveoli collapse with each breath.
As the alveoli collapse, damaged cells collect in the airways, which makes it even harder to breath.
These cells are called hyaline membranes.
hyaline
hualos = glass
hyaline
—> “having a glassy, translucent appearance.”
Hyaline Membrane Disease (HMD) ?
also called respiratory distress syndrome (RDS), is a condition that causes babies to need extra oxygen and help breathing.
one of the most common problems seen in premature babies ?
HMD is one of the most common problems seen in premature babies.
hyaline membrane disease (neonatal respiratory distress syndrome)
PATHOGENESIS
Prematurity (<36 weeks)
Multiple pregnancy/birth (more than one fetus)
Maternal diabetes
Cesarean Section
Amniotic fluid aspiration
maternal diabetes and NRDS (HMD)
Fetal hyperglycemia and hyperinsulinism secondary to maternal diabetes disrupt normal surfactant synthesis and function, which leads to surfactant inadequacy and clinical RDS in neonates.
C section – why risk factor for NRDS (?)
Cesarean section is a risk factor for RDS because the fetus absorbs about one-third of the fetal lung fluid during vaginal delivery,
whereas proper absorption of fetal lung fluid is not achieved in infants delivered through a cesarean section.
Amniotic fluid aspiration and NRDS
What Causes Meconium Aspiration Syndrome?
Meconium aspiration happens when a baby is stressed and gasps while still in the womb,
or soon after delivery when taking those first breaths of air.
When gasping, a baby may inhale amniotic fluid and any meconium in it.
meconium
the dark green substance forming the first feces of a newborn infant.
While babies most often hold out on pooping until they’re born, they are certainly active urinators in the womb.
placenta helps remove some of this waste naturally
Some pee will remain in the amniotic fluid, but it’s not considered dangerous for your baby like meconium can be.
mechanism / pathogenesis (NRDS)
immature/damaged type 2 pneumocytes
—> low level surfactant
—> lung collapse
—> hypoxia
–> alveolar lining damage / pulmonary vasoconstriction
–> endothelial damage
—> Fibrin Hyaline membranes
–> HYPOXIA (vicious cycle)
Sudden Infant Death Syndrome (SIDS)
Sudden unexpected death in infants between the ages of 2 – 9 months
SIDS aka
Also known as “crib death”
about
Seemingly healthy infants
Occurs during sleep
No obvious cause of death on autopsy
Most common cause of deaths in infants beyond neonatal period
SIDS
SIDS rate
Occurs in 1/500 births (according to Damjanov – may be outdated –> maybe closer to 1/1500 - 1/2000
most common in which groups?
Most common in young mothers, women of low socioeconomic status and education, smokers, substance abusers
other risk factors?
Genetic component
Premature infants at risk
Pathogenesis unknown
“Back to sleep” campaign has drastically reduced incidence
Back to sleep campaign
The Safe to Sleep campaign, formerly known as the Back to Sleep campaign
initiative backed by the US National Institute of Child Health and Human Development (NICHD)
encourage parents to have their infants sleep on their backs (supine position) to reduce the risk
Since “Safe to Sleep” was launched in 1994, the incidence of SIDS has declined by more than 50%.
leading causes of infant deaths in US, 2009
Birth defects = 5358
Low Birth Weight and Prematurity = 4528
SIDS = 2231
Maternal Complications = 1614
Accidents = 1172
Fluid and Hemodynamic disorders
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about water in body
Water – 60% of total body weight
2/3 – intracellular
1/3 – intercellular spaces; blood (80/20 plasma)
“Blood fluids must be in counterbalance with other fluid compartments”
overhydration vs dehydration
When boundaries of normal variation exceeded – overhydration, dehydration occurs
factors related to fluid dynamics
Factors to consider:
Redistribution of body fluids
Loss of fluids
Retention of fluids
Disruption of circulation
Edema define
Definition: excess fluid in tissues or body cavities
local or general?
Localized or generalized
general edema is called
Anasarca – generalized edema
Anasarca etymology
From Ancient Greek ἀνα- (ana-, “up to, thoroughly”) + σάρξ (sárx, “flesh, body”), short for ὕδρωψ ἀνὰ σάρκα (húdrōps anà sárka, literally “dropsy throughout the flesh”). Compare hyposarca.
dropsy define
An old term for the swelling of soft tissues due to the accumulation of excess water.
Edema in specific regions/organs
Cerebral edema - brain
Pulmonary edema - lungs
Macular edema - eyes
Ascites - edema within the peritoneal cavity
Pleural effusions - edema in the pleural cavity
(note joint effusions)
ascites
the accumulation of fluid in the peritoneal cavity, causing abdominal swelling.
ascites:
askos = wineskin
types of edema ??
Exudate vs Transudate
Exudate (edema)
High in protein and cells
Typical of inflammation
Transudate (edema)
High in protein (but less than exudate)
Low in cells
Transudate may accumulate due to the following:
1) increased hydrostatic pressure
2) reduced oncotic pressure
3) lymphatic obstruction
—> (FLUID FROM BV to TISSUE to LYMPH – but if lymph blocked, then fluid stays in tissue)
4) sodium retention
osmotic vs hydrostatic pressure
Whereas hydrostatic pressure forces fluid out of the capillary, osmotic pressure draws fluid back in.
Osmotic pressure is determined by osmotic concentration gradients, that is,
the difference in the solute-to-water concentrations in the blood and tissue fluid.
mroe about fluid in BV vs IS space
Fluid in circulating blood is separated from interstitial fluid by blood vessel wall (semipermeable membrane)
Movement across this barrier is determined by several factors (HS pressure, oncotic pressure, lymph blockage, sodium/ion retention
Hydrostatic pressure @ arterial end of capillary
vs
@ venous side of capillary
At the arterial end of a capillary, hydrostatic pressure exceeds the hydrostatic pressure on the venous side of the capillary promoting the passage of fluids into the interstitial fluid
I.e.
more fluid exiting capillaries (transudate?) @ arterial end of capillary
—> (greater pressure)
About Oncotic pressure
Aka colloid osmotic pressure
The pressure due to the presence of colloids in the blood
Colloids – any large molecule such as starch or protein
Colloids act like a sponge
so then why edema?
Edema occurs as a result of imbalance between forces that keep the fluid in the vessels and those that promote its exit into the tissues.
other classification for edema
Inflammatory edema
Hydrostatic edema
Oncotic edema
Obstructive edema
Hypervolemic edema
Inflammatory edema
Inflammatory edema: fluid leaks through the vessel wall which has been made more permeable
Hydrostatic edema
intravascular pressure promotes the transmembranous passage of fluids
oncotic edema
Oncotic edema: decreased plasma proteins or decrease in colloid osmotic pressure
Particularly proteins
Specifically albumin
obstructive edema
Obstructive edema: very rare; can be caused by parasites or worms (Africa) or tumour cells
(lymphatics obstruction)
why lymphatic edema?
parasites/worms
tumours cells
hypervolemic edema
kidney dysfunction leading to the retention of sodium and water
edema factors
Edema is usually multifactorial
Combination of many factors
Clinically important finding that may indicated dysfunction of major organs including kidneys and heart
note heart and edema
Congestive heart failure = edema in lungs or extremities
clinical types of edema (via edema @ specific location/organ)
Cerebral edema
Pulmonary edema
Pitting edema of lower extremities
Periorbital (facial) edema
Hydrothorax
Hydroperitoneum (ascites)
Anasarca
“pitting” edema
Pitting edema occurs when excess fluid builds up in the body, causing swelling;
when pressure is applied to the swollen area, a “pit”, or indentation, will remain.
Although it can affect any part of the body, pitting edema usually occurs in legs, feet, and ankles.
Hyperemia
“Too much blood”
Increase of blood flow to different tissues in the body due to the presence of metabolites and/or a change in general conditions
3 types of hyperemia
- Active
- Reactive
- Passive
active hyperemia
Aka functional hyperemia
The increased blood flow that occurs when tissue is active and requires more metabolites
Typically occurs during blushing, exercise or acute inflammation
when does active hyperemia typically occur?
blushing, exercise or acute inflammation
reactive hyperemia
Occurs in response to a profound increase in blood flow to an organ after being occluded
There will be a shortage of oxygen and a build-up of metabolic waste
E.g.
ischemic compressions (technique)
Passive hyperemia
Aka congestion
Caused by increased venous backpressure
Typically a consequence of heart failure
Often occurs in chronic form
Can lead to cyanosis (bluish tissues)
example of reactive hyperemia
ischemic compressions
typical of passive hyperemia
E.g. CHF
Passive Hyperemia is when parts of the body are clogged, or the blood is clotted and can’t flow. These conditions happen within your blood and organs, and may include: Heart failure
cyanosis typical of
& define
typical of passive hyperemia
define:
a bluish discoloration of the skin resulting from poor circulation or inadequate oxygenation of the blood.
Hemorrhage define
Loss of blood from the circulatory system
Can occur internally - blood leaks from blood vessels inside the body
Can occur externally, either through a natural opening such as the mouth, or through a break in the skin
internal vs external hemorrhage
”
how much blood loss can typcially be endured?
Loss of 10-15% of total blood volume can be endured without clinical consequences
(blood donation typically takes 8-10% of the donor’s blood volume)
when does hemorrhage become life-threatening
Hemorrhage becomes dangerous, or fatal, when it causes hypovolemia (low blood volume) or hypotension (low blood pressure)
how much blood loss fatal
Losing (40-)50% of the blood in your body may be fatal, but minor blood loss doesn’t pose any lasting risk to your health.
You can generally lose about 14% of the blood in your body without any major side effects, though you may feel dizzy or lightheaded.
If you lose more than 40 percent of your blood, you will die. This is about 2,000 mL, or 0.53 gallons of blood in the average adult. It’s important to get to a hospital to start receiving blood transfusions to prevent this.
hypovolemia define
a decreased volume of circulating blood in the body.
If you have hypovolemia, you lose more than 15% of the total volume of fluid within your circulatory system
Immediate treatment for hypovolemia is necessary to prevent life-threatening complications like organ damage, shock or death.
hypotension
Hypotension is a decrease in systemic blood pressure below accepted low values. While there is not an accepted standard hypotensive value, pressures less than 90/60 are recognized as hypotensive.
Severe hypotension (shock) can be caused by sudden loss of blood (shock), severe infection, heart attack, or severe allergic reaction (anaphylaxis).
“If your blood pressure drops too low, your body’s vital organs may not get enough oxygen and nutrients, which can lead to a medical emergency”
classification of hemorrage via duration and source/location
DURATION:
Acute
Chronic
Recurrent
SOURCE:
Cardiac
Aortic
Arterial
Capillary
Venous
Cardiac hemorrhage
May result from gunshot or stabbing
May result from softening of heart wall through myocardial infarct
Often fatal
Aortic hemorrhage
Often caused by trauma (e.g. car accident)
Can occur due to aortic wall weakening and dilation (aortic aneurysm)
Arterial hemorrhage
Caused by penetrating wounds from gun or knife
Can also occur due to fracture
danger of arterial blood loss (arterial hemorrhage)
NOTE:
Arterial blood is bright red and under pressure (pulsating); arterial blood loss often fatal
capillary hemorrhage
Marked by pinpoint droplets of blood appearing on mucosa or skin or tissues
Can be related to trauma, increased venous pressure, weakening of capillary walls, Vitamin C deficiency
Venous hemorrhage
Usually traumatic
Dark red or bluish
Not pulsating
other terms/definitions
Hemothorax - blood in thoracic cavity
Hemoperitoneum - blood in peritoneal cavity
Hemopericardium - blood in the pericardial cavity
Hematomas - blood filled swellings
—> “a solid swelling of clotted blood within the tissues.”
Petechiae
small hemorrhages of skin and mucosa
“dots”
petecchia = freckle/dot
Purpura
medium hemorrhages of skin and mucosa
4-10 mm in diameter
—> smaller than 4mm = petechiae
—> larger than 10mm = ecchymosis
purpura = PURPLE
ecchymoses
large blotchy bruises
hemoptysis
blood in respiratory tract, coughing up blood,
can be due to lung cancer, TB, etc.
hemoptysis etymology
hemo = blood
ptysis = Ptysis is Greek for Latin sputa {“spit, spittle”} or sputamina meaning the same.
Hematemesis
vomiting blood;
can be due to esophageal cancer
hemato
emesis = vomiting
emein = to vomit
Melena
black, discoloured blood in stool;
can be due to stomach cancer
Melena – WHERE does the bleeding occur?
“Melena” is the medical term for the black, tarry stool that
comes from bleeding in your upper gastrointestinal (GI) tract.
Black stool is a sign of OLDER blood in your stool.
melena etymlogy
melas = black
Hematochezia
anorectal bleeding;
can be due to hemorrhoids
hematochezia – where does blood come from
lower GI bleeds
hematochezia etymology
The term is from Greek αἷμα (“blood”) and χέζειν (“to defaecate”).
Hematochezia is commonly associated with lower gastrointestinal bleeding
hemorrhoids define
Hemorrhoids (HEM-uh-roids), also called piles, are swollen veins in the anus and lower rectum.
Hemorrhoids are similar to varicose veins.
Hemorrhoids can develop inside the rectum, called internal hemorrhoids.
They also can develop under the skin around the anus, called external hemorrhoids.
hemorrhoid etymology
from haima ‘blood’ + an element related to rhein ‘to flow’.
metrorrhagia
Metrorrhagia – uterovaginal bleeding; can be due to cervical or uterine cancer
metro:
“a combining form meaning ‘uterus,’”
menorrhagia
heavy menstrual bleeding; can be due to endometriosis
endometriosis define
a condition resulting from the appearance of endometrial tissue outside the uterus and causing pelvic pain.
endometrial tissue / endometrium
The layer of tissue that lines the uterus
hematuria
Hematuria – blood in urine; can be due to kidney infection
“clinical correlation”
Depend on:
Amount of blood loss
(Duration)
Site of hemorrhage
Other factors
Massive Acute hemorrhage
Potential life-endangering event
Up to 500mL loss – no consequences
1000-1500mL – shock
More than 1500 - lethal
(40% = 2000mL)
Chronic hemorrhage
E.g.
Bleeding gastric ulcer
Heavy menstruations
Result in anemia
other clinical correlations
Extravasated blood can damage tissues
Large hematomas are space occupying lesions
Can compress normal structures (MASS EFFECT?)
Can cause pain
mass effect hematoma E.g.
The hematoma can exert a mass effect on the brain, increasing intracranial pressure and potentially causing midline shift or deadly brain herniation.
Lecture 7 – genetic and developmental diseases
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about normal embryonic development
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zygote
Fertilization between egg and sperm yields zygote
zygote define
a diploid cell resulting from the fusion of two haploid gametes; a fertilized ovum.
what does zygote cell divide into
Zygote cells divide to form morula
morula define
A morula (from Latin “morus” meaning mulberry) is an embryo at an early stage of embryonic development, consisting of approximately 8–32 cells (called blastomeres).
blastomere
In biology, a blastomere is a type of cell produced by cell division (cleavage) of the zygote after fertilization; blastomeres are an essential part of blastula formation, and blastocyst formation in mammals.
blastula deifne
an animal embryo at the early stage of development when it is a hollow ball of cells.
morula vs blastula (vs gastrula vs blastocyst)
When a solid, compact cluster of 16 cells is present, which occurs at about 3 days post-fertilization in human beings, the zygote becomes a morula.
After several more cellular divisions, the morula becomes a hollow ball called a blastula.
(The gastrula develops from the hollow, single-layered ball of cells called a blastula)
In mammals, the blastula structurally reorganizes into a blastocyst.
morula (—> blastula —> gastrula) —> blastocyst
Morula transforms into blastocyst
blastocyst invading uterine wall —> development of three GERM LAYERS
The second and third weeks of embryological development are crucial, involving the implantation of the blastocyst into the uterine wall
the establishment of three distinct germ layers - the mesoderm, endoderm and ectoderm - through gastrulation
gastrulation define
the process by which a gastrula forms from a blastula.
gastrula
The gastrula develops from the hollow, single-layered ball of cells called a blastula which itself is the product of the repeated cell division
gastrula vs blastocyst
Blastocyst is an early embryonic stage in mammals (otherwise it is a blastula), which is followed by development of gastrula.
blastocyst / germ layers
Inner cell mass gives rise to primordial germ layers: ectoderm, endoderm, mesoderm
(after invading uterine wall)
fetal organs
Fetal organs and tissues including
muscle,
bone,
nervous tissue,
develop from primary germ layers
critical stage of ORGANOGENESIS
Characterized by extensive cell division, migration and cell-to-cell interaction
Developing organs very sensitive to external influences
what are exernal influences that affect developing organs?
what is TERATOLOGY
most importantly, chemical, physical and viral agents
Disturbance in development is called teratology
teratology define
the scientific study of congenital abnormalities and abnormal formations.
teratogen
Teratogen – causes fetal abnormalities
“an agent or factor which causes malformation of an embryo.”
fetal abnormalities etiology percentage
75% of cases idiopathic, 20% genetic diseases
(2% chromosomal abnormalities,
2% infections,
1% chemicals)
chromosomal abnormalities vs genetic disorders
Inherited disorders are caused by gene mutations. These include disorders such as cystic fibrosis, sickle cell disease, and Tay-Sachs disease.
Chromosomal abnormalities occur when there are missing or extra chromosomes or pieces of chromosomes.
(Those that produce changes in a single gene are known as gene mutations. Those that produce changes in whole chromosomes are known as chromosomal mutations.)
exogenous teratogens (physical)
X-rays
Radiation – gamma, beta, alpha rays
exogenous teratogens (chemical)
Many man made and many exists in nature (e.g. Thalidomide)
Most important - alcohol
thalidomide tragedy
Thalidomide was a widely used drug in the late 1950s and early 1960s for the treatment of nausea in pregnant women.
It became apparent in the 1960s that thalidomide treatment resulted in severe birth defects in thousands of children.
“Thalidomide is a known human teratogen and carries an extremely high risk of severe, life-threatening birth defects if administered during pregnancy.”
effects of exogenous teratogens
Can result in Fetal Alcohol Syndrome (FAS)
Causes intrauterine growth delay
Affects development of brain
Typical facial features include small cranium and jaw, thin upper lip
Reduced mental processes, low IQ
FAS ?
via exogenous teratogens
thin upper lip
can be via exogenous teratogens
note physical features of FAS
low nasal bridge
EPICANTHAL FOLDS (“upon” canthus/corner of eye)
Small eye opening
clinodactyly of 5th digit
indistinct PHILTRUM
short nose
underdeveloped jaw
thin upper lip
clinodactyly
a word derived from the Greek kliner, “to bend,” and dactylos, “a finger.”
exogenous teratogens (microbial)
Can affect fetus directly or indirectly
Indirect effects from weakening or exhausting of mother causes decrease in fetal weight, growth retardation, premature birth
Human pathogens that are especially noxious to fetus include:
human pathogens that are microbial teratogens
TORCH group:
Toxoplasma,
O
rubella,
cytomegalovirus (CMV),
herpes simplex,
O = Other
(Epstein-Barr virus, varicella virus, other bacteria)
what can torch group (microbial teratogens) do?
Several internal organs can be affected including the brain
effects of toxoplasmosis (and CMV) as a microbial teratogen
Toxoplasmosis and CMV –
characteristic abnormalities in brain,
small eyes with inflammation,
cataracts and calcifications
effects of Rubella (virus) as a microbial teratogen
Rubella –
brain is small (microcephaly) and often structurally abnormal;
heart defects;
inflammation of liver,
lungs,
enlarged spleen and lymph nodes
effects of CMV as a microbial teratogen
above
effects of herpes virus as a microbial teratogen
Herpes virus – skin lesions
why do symptoms/effects occur on fetus during infection of mother?
All symptoms related to transplacental passage of infectious agent during organogenesis
what were the exogenous teratogen types?
physical
chemical
microbial (viral?)
ENDOGENOUS TERATOGENS
Genetic factors
what can happen to fetus?
Often fetus is not viable resulting in spontaneous abortions (miscarriage)
other things that can happen (E.g.)
Other examples include cleft lip (multifactorial) and achondroplasia (autosomal dominant).
chromosomal abnormalities
..
human genes encoded by…?
what about chromosomes…?
Human genes encoded by triplets of nucleotides
Double-helix DNA condense into chromosomes during meiosis
normal human cells contain
Normal human cells contain 23 chromosome pairs –
22 autosomes and 2 sex chromosomes (XY male, XX female)
chromosomes inherited from
One set of 23 inherited from mother and one from father
Paternal sperm determines sex
how does sperm determine gender?
Every egg has an X sex chromosome; a sperm can have either an X or a Y sex chromosome.
If the sperm that fertilizes an egg has an X chromosome, the baby is female; if it has a Y chromosome, the baby will be a boy.
what are types of chromosomal abnormalities?
structural
numerical (trisomy (+1) or monosomy (-1))
types of structural chromosomal abnormalities
can be:
A) DELETION
B) TRANSLOCATION
which chromosomes can be involved during chromosomal abnormaltiies
Chromosomal abnormalities can involve:
autosomes
or
sex chromosomes (XX, XY)
Trisomy 21 (Down’s Syndrome)
Diagnosed in 1/800 newborns
Involves characteristic physical and mental abnormalities
maternal or paternal origin?
Mostly maternal origin
what chromosomal abnormality can lead to Trisomy 21
Can be associated with:
A) translocation
(structural)
B) or three autosome 21
(Numerical – Trisomy)
Trisomy 21 Sx
Mental disability
Typical facial features – wide face, low-bridged nose, close set slanted eyes, large protruding tongue
Abnormal extremities – short arms and legs, wide hands, “simian crease,” short and crooked fifth finger
simian crease (SINGLE PALMAR CREASE)
The crease is most often referred to as a single palmar crease.
The older term “simian crease” is not used much anymore, since it tends to have a negative meaning
(the word “simian” refers to a monkey or ape).
There are typically two creases in the palm, but in some people, only one crease is present.
Trisomy 21 other symptoms/abnormalities (organs)
Defects of internal organs – heart defects,
infertility in males
Trisomy 21 other symptoms/abnormalities (blood)
Hematologic abnormalities – anemia, leukemia, immune deficiencies
trisomy 21 – life expectancy, mortality
Increased mortality
50 (white)
25 (black)
Trisomy 21 Dx
Chorionic villus biopsy
Amniocentesis
chorionic villus biopsy define
Chorionic villus sampling, sometimes called “chorionic villous sampling”, is a form of prenatal diagnosis done to determine chromosomal or genetic disorders in the fetus.
It entails sampling of the chorionic villus and testing it for chromosomal abnormalities
chorionic villus define
The chorionic villi are tiny projections of placental tissue that look like fingers.
They have the same genetic material as the baby. Testing may be done for other genetic defects and disorders.
chorionic
Chorion:
the outer membrane that surrounds the embryo of reptiles, birds, and mammals and that in mammals with a placenta contributes to the formation of the placenta.
Down’s syndrome (Trisomy 21) recap
Mental disability
Unique facial features
Eye abnormalities
Gaping mouth & large tongue
Heart diseases
Intestinal defects
Hand abnormalities
Abnormalities of toes (wide gap between 1st/2nd toes)
what about abnormality of SEX CHROMOSOMES
More common than autosomes
Less lethal, less miscarriage
E.g. of chromosome abnormality (NONDISJUNCTION)
female ovum with TWO X chromosome instead of one
and another ovum with NO X chromosomes instead of one
when ovum with TWO combines with sperm with X
= three X chromosomes (TRIPLE X syndrome)
when ovum with NO X combines with sperm with X
= XO (TURNER’S SYNDROME)
ovum with TWO combines with sperm with Y
= XXY
(Klinefelter’s syndrome)
Turner’s Syndrome
Monosomy X (45, X)
Affects 1/3000 newborns
Short stature, webbing of neck, abnormal extremities, broad chest, congenital heart disease
Normal female genital organs except for ovaries which do not develop normally
Turner’s Syndrome (monosomy X) puberty
Never experience puberty
(Most girls will need to be treated with estrogen at some point for a normal progression of puberty and sexual development.)
slides not entirely accurate
(secondary sex characteristics during Monosomy X)
Slides:
“Do not develop secondary sex characteristics”
“She can also take hormone therapy to develop secondary sex traits, such as breasts, pubic hair, and underarm hair.”
Also:
“Growth hormone and androgen therapy can increase the final adult height of a girl.”
monosomy x – fertility
Most girls with the syndrome won’t be able to have children (are infertile) as adults.
Most girls will need to be treated with estrogen at some point for a normal progression of puberty and sexual development.
monosomy X, heart, kidney, thyroid
Other common problems with TS affect the heart, kidney, and thyroid.
Turner’s Syndrome (monosomy X) recap
Short stature
Heart-shaped face
Webbing of neck
Heart disease
Broad chest
Cubitus valgus
Streak ovaries, hypoplastic uterus, amenorrhea
streak ovaries define
A developmental disorder characterized by the progressive loss of primordial germ cells in the developing ovaries of an embryo,
leading to hypoplastic ovaries composed of wavy connective tissue with occasional clumps of granulosa cells
hypoplastic deifne
a condition of arrested development in which an organ or part remains below the normal size or in an immature state
(HYPOPLASIA)
granulosa cells
Granulosa cells are a type of cell in your ovaries that produce hormones including estrogen and progesterone
Hormones released from the base of your brain (anterior pituitary) control the numbers and function of granulosa cells
amenorrhea
Uterine hypoplasia is the extreme of Mullerian duct anomalies (Class I) where there is a small uterus above the vagina and may cause primary amenorrhea.
primary vs secondary amenorrhea
Primary amenorrhea is defined as having no history of menstruation by the age of 15 years or 3 years after thelarche
secondary amenorrhea is defined as the absence of menses for ≥3 months in a woman with previously regular menstrual cycles
thelarche
from Ancient Greek θηλή (thēlḗ, “nipple”) + Ancient Greek ἀρχή (arkhḗ, “beginning, onset”).
the beginning of breast development at the onset of puberty
Klinefelter’s Syndrome
47, XXY
Infertile males
Testis are atrophic and unable to produce sperm
Secondary sex characteristics do not develop at puberty
Penis is small and pubic hair is scant
Tall, female characteristics, gynecomastia
Klinefelters (XXY) features
Tall, long arms & legs
Lack of beard, body hair, pubic hair
Gynecomastia
Femalelike hips
Testicular atrophy, infertility
SINGLE-GENE DISORDERS***
…
about single gene disorders
Single genes are encoded by nucleotide triplets that occupy defined loci on the chromosomes
Genes located on the autosome all expressed in duplicate – alleles
Can be either dominant or recessive
Dominant overshadow recessive
locus/loci (genes)
The physical location of a specific gene on a chromosome.
allele define
one of two or more alternative forms of a gene that arise by mutation and are found at the same place on a chromosome.
dominant vs recessive genes
The most common interaction between alleles is a dominant/recessive relationship.
An allele of a gene is said to be dominant when it effectively overrules the other (recessive) allele.
A dominant allele produces a dominant phenotype in individuals who have one copy of the allele, which can come from just one parent.
For a recessive allele to produce a recessive phenotype, the individual must have two copies, one from each parent.
what if one dominant and one recessive?
One dominant and one recessive; express the dominant – heterozygous (sp?)
what about recessive?
Recessive only express if paired with another recessive – homozygous
heterozygous vs homozygous
If an organism has two copies of the same allele, for example AA or aa, it is homozygous for that trait.
If the organism has one copy of two different alleles, for example Aa, it is heterozygous.
xx vs xy – homozygous vs heterozygous
Mammalian sex is determined genetically by the presence of X and Y chromosomes.
Individuals homozygous for X (XX) are female,
while heterozygous individuals (XY) are male.
what are the four ways human traits (genes?) can be expressed
(MENDELIAN INHERITANCE/GENETICS)
Autosomal dominant
Autosomal recessive
Sex-linked recessive
Sex-linked dominant (rare)
trait vs gene
A trait is a feature like height, eye color, etc. Genes code for proteins and proteins determine traits.
AUTOSOMAL DOMINANT INHERITANCE (DISORDERS)
Encoded by a gene that is located on one of the 22 autosomes and is dominant in relationship to its allele
Fully expressed in heterozygotes
The affected heterozygote has 50% chance of transmitting the gene to each offspring
E.g. of Autosomal dominant disorders
Marfan’s syndrome
(Connective Tissue)
Achondroplastic dwarfism (Achondroplasia)
—> bones
Osteogenesis imperfecta
—> “
Familial hypercholesterolemia
—> CV system
Adult polycystic kidney disease, Wilms’ tumor
—> kidneys
Spherocytosis
—> hematopoietic system
Huntington’s disease, Neurofibromatosis
—> nervous system
Familial polyposis coli
—> GI system
Marfan’s syndrome
Autosomal dominant disease
Affects 1/10,000 persons
Multisystemic disease
Marfan’s features
Skeletal changes – slender skeleton, elongated head, joints are loose, ligaments are weak, luxations, spinal deformities
Marfan’s and CV system
Cardiovascular changes - CT of large vessels is weak leading to aneurysms; faulty heart valves lead to heart failure
Marfan’s effects on vision
Ocular changes – subluxated lens, cataracts, retinal detachment, blindness
Marfan’s pathogenesis
Pathogenesis related to defect in gene that codes for fibrillin
fibrillin
Fibrillin is a glycoprotein, which is essential for the formation of elastic fibers found in connective tissue
Marfan’s recap
Elongated head
Eye abnormalities
Aortic aneurysm with dissection and exsanguination
Floppy mitral valve
Vertebral deformity
Long fingers (arachnodactyly)
Familial Hypercholesterolemia
Autosomal dominant
1/500 persons affected in US
Common cause of cardiovascular disease
Caused by mutation in gene encoding the receptor for low-density lipoprotein (LDL)
LDLs transport cholesterol (to tissue)
Familial hypercholesterolemia – pathogenesis
Receptor deficiency – LDL cholesterol removal from blood is less efficient
Leads to deposition of lipids in arteries (“clogged arteries”) leading to cardiovascular disease
Xanthomas – lipid-rich yellow nodules; consist of macrophages that have phagocytized cholesterol
Xanthoma
xanthos = yellow
oma
Xanthoma is a skin condition in which certain fats build up under the surface of the skin.
Xanthomas are raised, waxy-appearing, frequently yellowish-colored skin lesions.
They may be associated with an underlying lipid (cholesterol/triglyceride) abnormality.
Familial Hypercholeterolemia, Tx/prognosis
No cure
Progression of disease can be slowed by low-fat diet and drugs
AUTOSOMAL RECESSIVE DISORDERS
Encoded by genes located on one of the 22 autosomes
Only expressed under homozygous conditions
(Only expressed if one gene inherited from each parent)
NOTE:
PARENTS ARE USUALLY ASYMPTOMATIC CARRIERS
CARRIER
a person or other organism that possesses a particular gene, especially as a single copy whose effect is masked by a dominant allele, so that the associated characteristic (such as a hereditary disease) is not displayed but may be passed to offspring.
autosomal recessive disorders (E.g.)
Cystic fibrosis
Anemias
—> Sickle cell anemia
—> Thalassemia
Lipidoses
—> Tay-Sachs disease
—> Niemann-Pick disease
Mucopolysaccharidoses
—> Hurler’s syndrome
—> Hunter’s syndrome
Amino acid disorders
—> Phenylketonuria
—> Albinism
Cystic fibrosis (CF)
Most common autosomal recessive disorder in US
1/2500 neonates in US
1/25 person estimated carrier
Almost exclusively seen in Caucasians
Affected gene codes for chloride transport channel in cell membrane
most common autosomal; recessive disorder
CF
which ethnicity CF
Almost exclusively seen in Caucasians
CF pathogenesis
abnormal chloride transport = VISCID (thick) MUCUS
—> malabsorption via pancreas (MALABSORPTION)
—> MECONIUM ILIUS @ fetal intestine
—> bronchitis @ bronchi (PNEUMONIA)
Can all lead to death
meconium ileus
Meconium ileus is a bowel obstruction that occurs when the meconium in your child’s intestine is even thicker and stickier than normal meconium, creating a blockage in a part of the small intestine called the ileum.
Most infants with meconium ileus have a disease called cystic fibrosis.
CF more about PATHOGENESIS
Leads to lack of NaCl in glandular secretions in all exocrine glands
Leads to less water in secretions – more viscous
Viscous mucous leads to obstruction of organs
Obstruction in pancreas – enzymes don’t flow into intestine
CF malabsorption
Leads to malabsorption of nutrients
Stools are bulky, greasy and malodorous
Children often show growth abnormalities
CF lungs
Most important complication involves bronchial mucosa
Bronchial mucous plugs prevent normal respiration
viscid mucus & bacteria growth
Mucous provides fertile growth medium for bacteria
Affected individual presents with recurrent bacterial infections, chronic bronchitis, recurrent pneumonia
CF and sweat glands
Sweat glands are affected
CF fertility and other facts
Males often infertile
No cure
why CF male infertility
Infertility in men with CF occurs because of an absence of the sperm canal.
Lysosomal storage disease
Related to deficiency of enzymes involved in intermediary metabolism
Metabolites that cannot be fully degraded, digested or incorporated get stored in lysosomes
Lysosomal storage diseases classified based on primary pathway affected; or on eponyms
E.g. of lysosomal storage diseases
E.g. lipidosis, glycogenosis, mucopolysaccharidosis, Tay-Sachs, etc.
Tay-Sachs disease
Tay-Sachs is a defect in the function of hexosaminidase A resulting in accumulation of ganglioside
hexosaminidase A
either of two hydrolytic enzymes that catalyze the splitting off of a hexose from a ganglioside and are deficient in some metabolic diseases (such as Tay-Sachs disease)
hexose define
ganglioside define
hexose:
any of the class of simple sugars whose molecules contain six carbon atoms, such as glucose and fructose. They generally have the chemical formula C6H12O6.
ganglioside
any of a group of complex lipids which are present in the gray matter of the human brain.
OTHER DEFINITION:
“A complex molecule that contains both lipids (fats) and carbohydrates (sugars) and is found in the plasma (outer) membrane of many kinds of cells.”
COMMON FEATURE OF ALL LYSOSOMAL STORAGE DISEASES
All LSDs characterized by accumulation of metabolites that cannot be processed due to inherited gene defect
Lysosomal storage diseases, Symptoms
Symptoms are variable
Can be mild or lethal
Include splenomegaly, anemia, deformities, neurologic symptoms, etc.
lysosomal storage diseases, Diagnosis
Diagnosis can be done in utero
lysosomal storage disease, a note about mechanism
in normal metabolism, enzyme digests contents of lyososome
In LSD, enzyme is not functional / absent (?)
contents are abnormally stored
PHENYLKETONURIA (PKU)
Congenital defect of phenylalanine hydroxylase (PAH), an enzyme that metabolizes phenylalanine into tyrosine
IMPORTANCE OF TYROSINE
for MELANIN, DOPAMINE production
and for proteins
tyrosine define
a hydrophilic amino acid which is a constituent of most proteins and is important in the synthesis of some hormones.
phenylalanine hydroxylase
and
phenylalanine
Phenylalanine hydroxylase is responsible for the conversion of phenylalanine to another amino acid, tyrosine.
phenylalanine
Phenylalanine is an amino acid, a building block of protein. Most people don’t need to worry about it.
But it is an issue for people who have a genetic condition called phenylketonuria (PKU).
note normal vs abnormal metabolism
dietary protein —> phenylalanine —> TYROSINE (via phenylalanine hydroxylase)
However, w/ PHENYLKETONURIA, Phenylalanine gets converted to
—> PHENYLPYRUVIC ACID
PHENYLPYRUVIC ACID
When the activity of the enzyme phenylalanine hydroxylase is reduced, the amino acid phenylalanine accumulates and gets converted into phenylpyruvic acid (phenylpyruvate),
which leads to ‘Phenylketonuria (PKU)’ instead of ‘tyrosine’ which is the normal product of phenylalanine hydroxylase.
phenylpyruvic acid in blood
The presence of this acid in blood and tissues causes mental retardation
PKU prognosis
If treatment is delayed or the condition remains untreated, brain damage will occur. School functioning may be mildly impaired.
If proteins containing phenylalanine are not avoided, PKU can lead to mental disability by the end of the first year of life.
Phenylketonuria, other important notes
Phenylalanine ingested from food cannot be metabolized and accumulates in blood and tissues
Phenylalanine also gets converted into phenylpyruvic acid and phenylketones which get excreted in urine
PKU more about prognosis
Children born with PKU initially healthy
Diagnosis done at birth by mandatory routine screening
Special phenylalanine free diet prescribed will ensure normal neural development
Normal diet results in slow, progressive, irreversible mental disability
X-LINKED RECESSIVE DISORDERS ***
Encoded by recessive genes located on X but not Y chromosome
Rarely expressed in females
Gene is transmitted from asymptomatic mother
Examples include hemophilia and muscular dystrophy
E.g. X-linked recessive disorders
Duchenne’s MD
Wiskott-Aldrich syndrome
Agammaglobulinemia
X-linked immunodeficiency
Lymphoproliferative syndrome
Hemophilia B
Fragile X
Hemophilia A
Red-green colour blindness
X-linked recessive disorders, examples on slides
—> Muscular dystrophy
Hemophilia A & B
Duchenne’s
Becker’s
Agammaglobulinemia
Wiskott-Aldrich syndrome
X-linked immunodeficiency
Lymphoproliferative disorders
Hemophilia
Hereditary bleeding disorder linked to mutations of genes that code for
Coagulation factor VIII (hemophilia A)
Affects 1/5000 boys
Hemophilia A severity
Mild to severe symptoms depending on extent of defect
Asymptomatic or severe bleeding disorder
Hemophilia A rate
Affects 1/5000 boys
Hemophilia, which coagulation factor is affected
Coagulation factor VIII
Hemophilia B
Coagulation factor IX (hemophilia B)
Always severe bleeding disorder
Hemophilia A and B:
—> Internal hemorrhage common
—> Deformity of joints common
—> Hemorrhage may be spontaneous or follow minor trauma
can hemorrhage be spontaneous (apparently no reason) in hemophilia
yes
Hemophilia Tx
Treatment of hemophilia includes blood transfusions and administration of deficient clotting factors
MD
Characterized by progressive wasting of muscles
Linked to a genetic defect
Affects males
Rarely affects females
MD pathogenesis
Gene for MD codes for dystrophin, a structural cell protein forming a network beneath the plasma membrane that interacts with other cytoskeletal and contractile proteins
(Connects thin filament to sarcolemma)
Without dystrophin, the cells cannot retain their proper form or adapt to stress and tend to disintegrate
MD consequence
Consequences most prominent in skeletal muscles
Duchenne-type dystrophy
Most affected born to asymptomatic parents
Mother is usually carrier (If father had gene defect, they would have the disease – only 1 X)
MD prognosis
Symptoms become evident in early infancy
Children generally in wheelchair with marked deformities
Many die in late teens
Becker’s?
Less incapacitating
Life expectancy into 40’s – 50’s
MULTIFACTORIAL INHERITANCE
Familial diseases not inherited according to rules of Mendelian genetics
Such diseases are products of several genes that interact with each other and are also influenced by exogenous factors (Environmental factors)
E.g. multifactorial genetics
E.g. diabetes, hypertension
Anencephaly (E.g. multifactorial development defect)
Example of multifactorial developmental defect
Occurs due to incomplete fusion of midline structures covering brain: meninges, bones of calvarium, overlying skin
—> NEURAL TUBE DEFECT
Development of brain and spinal cord severely disturbed
Child is born severely malformed with no brain or partial brain
about anencephaly
Anencephaly is a fatal condition where a baby is born without parts of the brain and skull.
It is a type of neural tube defect (NTD). There is no known cure or standard treatment for anencephaly.
(During early pregnancy, the neural tube develops into the baby’s brain and spine.)
note neural tube defects
Outcome of altered activity of many genes results in spectrum of disorders ranging from major defects to minor defects of vertebral bones (spina bifida occulta)
Predilection for gene malfunction is heritable
Folic acid may reduce risk
Diabetes Mellitus (multifactorial inheritance)
Disturbance of intermediate metabolism resulting in hyperglycemia
Occurs more often in some families
Adult-onset disease called type II or noninsulin-dependent diabetes mellitus (NIDDM)
Multifactorial disease with genetic component; development of disease depends on diet, obesity, sedentary lifestyle
(ENVIRONMENTAL FACTORS)
PRENATAL DIAGNOSIS **
Important element of genetic counseling
Can be diagnosed while fetus is in early stages
Ultrasonographic examination
Can detect malformations of head, extremities, internal organs; placenta
Chorionic villus biopsy
Placental biopsy
Provide fetal cells for chromosomal analysis or for biochemical testing
Amniotic fluid analysis
Fluid aspirated from amniotic sac during 12-18th week; chemical or genetic analysis
Maternal blood analysis
High levels of AFP common in certain fetal abnormalities
(ALPHAFETOPROTEINS)
Triple-screen marker test – measures maternal AFP, human chorionic gonadotropin and unconjugated estriol
note other significance of AFP
An AFP (alpha-fetoprotein) tumor marker test measures AFP in your blood. High levels may be a sign of cancer of the liver
“High levels of AFP may be a sign of cancer of the liver, ovaries, or testicles. But having a high AFP level doesn’t mean you have cancer or that you will get cancer.”
“Liver injury and liver diseases that aren’t cancer can also cause high AFP levels”
HCG (human chorionic gonadotropin) test
Quantitative HCG measurement helps determine the exact age of the fetus.
It can also assist in the diagnosis of abnormal pregnancies, such as ectopic pregnancies, molar pregnancies, and possible miscarriages.
unconjugated estriol
The Estriol Unconjugated test is usually done as part of a series of tests known as maternal serum screening, which are used to screen for certain birth defects and chromosomal abnormalities in the fetus.
“Unconjugated Estriol is a form of estrogen (a hormone) developed by the fetus (the unborn baby) through metabolism. Estriol levels help to determine birth defects and chromosomal discrepancies in babies.”
….
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PHARMACOLOGY 2
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how are drugs administered to body?
..
admiistration types
Oral administration
Application to mucous membranes
Topical applications
Parenteral administration
Implanted catheters and drug pumps
how effects?
changes:
a) bioavailablity
b) onset of action
c) intensity
most popular?
oral administration
mechanism?
Medication is swallowed in prescribed dose and absorption occurs into the blood from the GI tract
how does form alter absorption / distribution
SOLID VS LIQUID?
minutes vs hours
Depending on its form (solid or liquid) it can take between minutes and an hour before the drug is absorbed and distributed in the blood and exert its effects
Solid oral??
First pass effect
Solids typically dissolve in the stomach and are absorbed in the intestines….
PROBLEM? Subject to first-pass metabolism (???)
—> More a problem of oral (vs solid) (???)
first pass effect (first pass metabolism)
“The first-pass metabolism or the first-pass effect or presystemic metabolism is the phenomenon which occurs whenever the drug is administered orally, enters the liver, and suffers extensive biotransformation to such an extent that the bioavailability is drastically reduced, thus showing subtherapeutic action”
first pass effect 2
The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism at a specific location in the body which leads to a reduction in the concentration of the active drug before it reaches the site of action or systemic circulation.
first pass effect 3
The effect is most associated with orally administered medications, but some drugs still undergo first-pass metabolism even when delivered via an alternate route (e.g., IV, IM, etc.).
During this metabolism, drug is lost during the process of absorption which is generally related to the liver and gut wall. The liver is the major site of first pass effect; however, it can also occur in the lungs, vasculature or other metabolically active tissues in the body.
why is it called first pass effect/metabolism
The drugs then must pass through the liver before reaching the systemic circulation.
This “first-pass” through the liver provides an opportunity for the liver to metabolize and inactivate/eliminate the drug before it reaches the systemic circulation.
oral dose should be
If a drug undergoes significant first-pass metabolism, a much larger dose of the drug is needed when it is given orally than when it is given by other routes.
enteric coated tablets
Enteric coated tablets have a specific layer of material to protect against gastric acids
Allows medication to dissolve in the intestine instead of the stomach
May take longer to be absorbed
where dissolve instead
They then dissolve in the less acidic small intestine to be absorbed.
survive intact as they pass through the acidic stomach
time-released / time-controlled pills
Time release/controlled means small amounts of the medication will be released into the persons system over a longer period of time
why time-released ?
Allows for constant level of medication in the blood
what about the absorption / onset of liquid medication?
Liquid medications are generally absorbed into the circulation within 15 minutes and usually has a faster onset of action when compared to solids
2) APPLICATION TO MUCOUS MEMBRANES
..
what are mucous membranes?
what do they ocntain
where are they
Mucous membranes contain mucous-secreting cells and cover internal surfaces of body passages (digestive, respiratory, reproductive and urinary tracts)
what is the important structural feature of mucous membranes that is applicable to drug administration/aborption ???
Mucous membranes are highly vascularized with extensive networks of blood vessels that pose fewer restrictions to drug access
what situations is mucous membrane application superior?
note onset of action
Can be used to address infections and inflammations and can also be used when a systemic effect is needed with a more rapid onset of action
E.g.
angina attack-> application of nitroglycerine tablet under his/her tongue
—–> Tablet is absorbed across the membrane and enters the bloodstream and can relieve symptoms within minutes
suppository
a solid medical preparation in a roughly conical or cylindrical shape, designed to be inserted into the rectum or vagina to dissolve.
enema
a procedure in which liquid or gas is injected into the rectum, typically to expel its contents, but also to introduce drugs or permit X-ray imaging.
inhaler
a portable device for administering a drug which is to be breathed in, used for relieving asthma and other bronchial or nasal congestion.
Inhalers are small, handheld devices that allow you to breathe medicine in through your mouth, directly to your lungs.
sprays (?)
oral spray, sublingual powder, and sublingual tablets
(Nitroglycerin)
3) TOPICAL
a) Ear (otic)
b) Eye (ophthalmic)
c) Skin (dermal)
USUALLY FOR WHAT PURPOSE???
LOCAL COMPLAINTS
Usually used to treat local complaints such as ear infections, eye infections, and itchy skin/skin infections.
a) otic
Usually as drops (LIQUID DROPS) (droplets)
Are applied as close to body temperature as possible to avoid overstimulation of the auditory nerve
b) opthalmic
liquid drops
or
ointment
STERILE *****
Drops or ointments must be kept as sterile as possible because eyes are very susceptible to infection
eye drops STERILIZATION
If the drug is not stable at high temperatures, eye drops in solution form can be sterilised by filtration through a 0.22 μm filter into a sterile final container. This method is called filter sterilisation and it should be conducted under aseptic conditions using a laminar flow cabinet.
eye drops common side effect (???)
Eye medications may be followed by periods of blurred vision
Some drops can cause blurry vision for a few minutes after putting them in because they can cloud the tear film on the surface of your eye.
c) Dermal administration
Can be used to treat local skin conditions such as:
i) Rashes, dry skin, infections and abrasions
ii) Relief of muscle and joint pain
dermal (topical) for
i) Rashes, dry skin, infections and abrasions
Tend to contain antibiotics, antihistamines, corticosteroids, moisturizers and analgesics
Designed to absorb and act specifically on affected area
dermal (topical) for
ii) Relief of muscle and joint pain
Typically contain capsaicin, menthol, wintergreen, and oils that are quite volatile, and evaporate quickly
Typically contain capsaicin, menthol, wintergreen, and oils that are quite volatile, and evaporate quickly
capsaicin dermal (topical) cream
Capsaicin, a chili pepper extract, can stimulate increased skin blood flow (SkBF) with a perceived warming sensation on application areas. Larger surface area application may exert a more systemic thermoregulatory response.
menthol dermal (topical) medicine
MENTHOL
This medication is used to treat minor aches and pains of the muscles/joints (such as arthritis, backache, sprains). Menthol is known as a counterirritant. It works by causing the skin to feel cool and then warm. These feelings on the skin distract you from feeling the aches/pains deeper in your muscles and joints.
wintergreen (dermal) topical medication
Wintergreen oil is applied to the skin as a “counterirritant” to relieve muscle pain. Counterirritants work by causing irritation that reduces pain and swelling in the underlying tissue. Wintergreen oil is also used to kill germs on the skin.
dermal (systemic administration of drugs)
I.e.
DERMAL (topical) MEDICATION that is meant to be SYSTEMIC, NOT JUST LOCAL
TRANSDERMAL TOPICAL (dermal) CREAM
Typically involves “transdermal” meaning that the drug is formulated in a special gel-like matrix and is able to pass through the skin barrier and enter the systemic circulation
IMPORTANT NOTE ABOUT TRANSDERMAL PATCH
Should be aware that transdermal patches typically maintain a controlled medication level in the blood and implications of wiping it off or disengaging a patch can be serious
E.g. transdermal patch
nicotine
hormone replacement therapy
4) PARENTERAL
Typically referring to injections
“administered or occurring elsewhere in the body than the mouth and alimentary canal.”
“other than”
“enteral”
why parenteral?
When oral would be ineffective (Example: insulin would be destroyed by the stomach)
During an emergency (anaphylaxis)
Continuous, steady supply of a drug
Vaccines
An injection specifically into a tissue (intra-articular injection)
COMMON SITE FOR IM INJECTION/administration
(PARENTERAL)
Muscles commonly used for intramuscular injections are deltoids, gluts, and the quadriceps
5) IMPLANTED CATHETERS AND DRUG PUMPS
Used with patients with special requirements
implanted catheters
Surgically fitted so it is mostly lying beneath the skin
The entrance site is made in the tissue at the location where the drug is to be administered
If the drug must be delivered directly into the circulation, the catheter is usually placed into a central vein
The part between the entrance and exit site lies within a surgically created subcutaneous tunnel
Drug Pumps
Used to deliver medications into the bloodstream via an intravenous line or an implanted catheter
Can be external (where the patient pushes a button on the pump mechanism to release a predetermined dose of the medication into the bloodstream or internal (subcutaneously implanted and can stay in place for as long as 1-2 years)
clinical relevance (implanted catheters and drug pumps)
Knowing the route of administration can help to minimize any chances of medication-related adverse reactions
Those on anti-inflammatories may not be able to give accurate feedback regarding depth of treatment
Treatment around implanted catheters and drug pumps should be monitored by all involved in patient’s care
DRUG PROCESSING IN BODY
Once drugs are administered, they are subjected to certain physiological processes that can modify their capacity to affect their target cells.
WHAT ARE STEPS OF PROCESSING??
1) Dissolving and dissociating
2) Metabolism
3) Distribution
4) Elimination
1) Dissolving and dissociating
During manufacturing, several inactive substances called excipients are included in the preparations
excipient functions
2 functions:
To help preparation maintain its stability while being stored
To ensure that it can readily dissolve and dissociate in the GI tract
excipient
an inactive substance that serves as the vehicle or medium for a drug or other active substance.
dissolving / dissociating
Tablets and capsules that quickly dissolve and dissociate are more rapidly absorbed and increase the drug’s bioavailability and makes the onset of action faster
WHAT ABOUT LIQUDI MEDICAITON
Oral liquid medications contain the drug ingredients in a dissolved form, making them more readily available
WHAT VARIBABLE DETERMINE DISSOLVE DISSOCIATE, ABSORB
Chemical nature
Dosage
Form of administration
Size of its particles
Presence of any GI pathologies
2) METABOLISM
After being absorbed, a drug is transported to the liver via portal circulation
The liver is the most important organ of metabolism
FIRST PASS EFFECT
First pass effect: refers to the effects of liver processes on a drug that has just entered the blood from the GI tract
ARE ALL DRUGS AFFECTED BY LIVER
Not all drugs are affected by liver enzymes
If not affected by the liver, the drug is usually excreted or eliminated in its original form
METABOLISM
When a drug undergoes metabolic reactions, substances called metabolites are formed
METABOLITES
Metabolites are inactive and harmless, but some can have pharmacological effects and can either produce desired therapeutic effects or they may be responsible for undesired side effects
WHAT ARE METABOLITES, WHAT DO
Metabolites are inactive and harmless, but some can have pharmacological effects and can either produce desired therapeutic effects or they may be responsible for undesired side effects
HOW AVOID FIRST PASS EFFECT ???
CAN THEY TRULY AVOID??
SUBLINGUAL, IM, IV, SUPPOSITORY
Other routes of administration are used to make a drug available to its target tissue before breakdown can occur in the liver
Sublingual administration leads to absorption into circulation through the buccal mucous membranes
This is also true for suppositories, IV or intramuscular injections
can they FULLY avoid first apss effect?
They can bypass the first pass effect but will eventually get to the liver and be exposed to its enzymes
3) DISTRIBUTION
Refers to how a drug is transported from its site of absorption to its site of action, metabolism, and excretion
The following circulatory factors can affect drug distribution:
WHAT CIRCULATING FACTORS AFFECT DISTRIBUTION
i) Rate of blood flow to various tissues
ii) How much drug is bound to plasma proteins
iii) Mechanisms that control brain access
i) Rate of blood flow to various tissues
Organs that receive high volumes of blood (kidneys, liver, brain) will initially receive higher drug concentrations than tissues like fat and muscles
ii) How much drug is bound to plasma proteins
Drugs are typically bound to plasma proteins to form drug-protein complexes
Each drug has a characteristic degree of binding, yet there is constant movement of drug molecules from the bloodstream into the intercellular spaces
iii) Mechanisms that control brain access
BBB **************
Cells of the blood brain barrier identify substances that are potentially damaging and obstruct them from leaving the blood and entering the brain
Lipid soluble drugs cross the blood brain barrier much more easily than drugs with poor lipid solubility
BBB******** LIPID SOLUBILITY******* BRAIN ACCESS********* DISTRIBUTION
Lipid soluble drugs cross the blood brain barrier much more easily than drugs with poor lipid solubility
4) ELIMINATION
The liver prepares drugs and other toxic substances for elimination
The metabolites are biochemically altered to make them harmless to body tissue and more readily eliminated
MOSTLY VIA ????
Mostly accomplished by the kidney
ALSO
However, some drugs are excreted in bile and from sweat glands
METABOLISM VS ELIMINATION
Together, metabolism and elimination are the primary determinants of a drug’s half-life
CLINICAL RELEVANCE
During the production of solid oral preparations, the quality of excipients or inactive substances used by manufacturers varies (generic vs brand name)
A tablet that dissolves and dissociates poorly will not be absorbed as readily as a tablet of higher quality
Less absorption leads to lower bioavailability, slower onset of action, and questionable effectiveness
EXCIPIENT TYPE QUALITY, GENERIC VS BRAND NAME
…. **************
other CLINNICAL RELEVANCE
Health and function of the liver and kidneys are extremely important for the normal removal of drugs and other toxic substances from the body
Clients who are fasting or those with liver and kidney disease will often have a decrease in albumin therefore more free drug available for interaction with target cells (leading to increased effects of the drug)
