►►Antiviral Agents (Cont’d.)
GENERAL PRINCIPLES │ 5. Microbiology Class/Agent Mechanism of Action Spectrum/Clinical Mechanism(s) Toxicity/Notes
Applications of Resistance
HIV THERAPY: For details on HIV therapy, see Ch. 4, General Principles of Immunology
Interferons✝ Interferons are a class • Hepatitis B & C Anti-interferon • I nterferons can
of related proteins with • Kaposi sarcoma antibodies cause influenza-like
antiviral, antiproliferative, • L eukemias are seen with symptoms, especially
and immune regulating • M alignant prolonged use in the first week of
activity. They induce the therapy
synthesis of a number of melanoma
antiviral proteins (e.g., • Bone marrow
RNAse and a protein suppression
kinase) that protect the
cell against subsequent • Profound fatigue,
challenges by a variety myalgia, weight
of viruses. loss, and increased
susceptibility to
bacterial infections
• Depression is seen in
up to 20% of patients
Definition of abbreviations: CMV, cytomegalovirus; HCV, hepatitis C virus; HSV, herpes simplex virus; RSV, respiratory
syncytial virus; VZV, varicella zoster virus.
✝ For more information on interferons and other immunosuppressants, see Chapter 4, General Principles of Immunology
Mycology
►►Mycology: Overview
Fungi are eukaryotic organisms with complex carbohydrate cell walls (the reason they frequently calcify in chronic infections) and
ergosterol as their major membrane sterol (which is targeted with nystatin and the imidazoles). Morphologic and geographic clues are very
important in determining the identity of the organism.
Fungi come in two basic forms • Hyphaefilamentous forms may either have cross walls (septate) or lack them (aseptate)
• Yeastssingle-celled oval/round forms
• Dimorphic fungimay convert from hyphal to yeast forms (key examples: Histoplasma,
Blastomyces, Coccidioides, and Sporothrix).
Mnemonic: Heat Changes Body Shape: yeast in the heat, mold in the cold
Pseudohyphae • Hyphae formed by budding off yeasts; formed by Candida albicans; the basis of the germ tube
test for diagnosis of invasive C. albicans
Spores are used for reproduction • Conidiaasexual spores form off hyphae
and dissemination • Blastoconidiaasexual spores like buds on yeasts
• Arthroconidiaasexual spores formed with joints between
• Spherules with endosporessexual spores in tissues (Coccidioides)
136
►►Nonsystemic Fungal Infections
Organism Disease Notes GENERAL PRINCIPLES │ 5. Microbiology
Malassezia furfur Pityriasis or tinea • Superficial infection of keratinized cells
versicolor
• Hypopigmented spots on the chest/back (blotchy suntan)
• KOH mount of skin scales: “spaghetti and meatballs,” yeast clusters and
short, curved septate hyphae
• Treatment is topical selenium sulfide; recurs.
Fungemia • In premature infants
Candida albicans, Cutaneous or • Causes oral thrush and vulvovaginitis in immunocompetent individuals
Candida spp. mucocutaneous
candidiasis • Source of opportunistic infections in hospitalized and immunocompromised
(see Opportunistic Mycoses)
Pseudohyphae Budding Germ True
Yeasts Tubes Hyphae
Trichophyton, Microsporum, Tinea (capitis, • Infects skin, hair, and nails
Epidermophyton barbae, corporis, • Monomorphic filamentous fungi
cruris, pedis) • KOH mount shows arthroconidia, hyphae
Sporothrix schenckii • Pruritic lesions with serpiginous borders and central clearing
• Sporotrichosis
Hyphae with sleeves (rose gardener’s Dimorphic fungus:
disease) • Environmental form: hyphae with rosettes and sleeves of conidia
• Tissue form: cigar-shaped yeast
• Pulmonary
sporotrichosis
(in alcoholics/
homeless)
or rosettes of conidia
137
►►Systemic Fungal Infections
GENERAL PRINCIPLES │ 5. Microbiology Organism Disease Notes
General Comments
Histoplasma • Acute pulmonary Diagnosis:
Coccidioides (asymptomatic or self-
Blastomyces resolving in about 95% of the • Sputum cytology (calcofluor white staining helpful)
cases)
• Sputum cultures on blood agar and special fungal media
• Chronic pulmonary (inhibitory mold agar, Sabouraud’s agar)
• Disseminated infections • Peripheral blood cultures are useful for Histoplasma because it
circulates in RES cells
Specific Organisms
Histoplasma capsulatum Fungus flu (a pneumonia) Dimorphic fungus:
• Asymptomatic or flu-like • Environmental form: hyphae with microconidia and tuberculate
macroconidia
• Hepatosplenomegaly may be
present − Endemic region: Eastern Great Lakes, Ohio, Mississippi, and
Missouri River beds
• May disseminate in AIDS
patient − Found in soil (dust) enriched with bird or bat feces
(caves, chicken coops)
• Tissue form: small intracellular yeasts with narrow neck on bud; no
capsule
• Facultative intracellular parasite found in RES cells (tiny;
can get 30 or so in a human cell)
Coccidioides immitis Coccidioidomycosis • Dimorphic fungus
(San Joaquin Valley fever) • Asymptomatic to self-resolving pneumonia
• Desert bumps (erythema nodosum)
(endospores/spherules)
• Pulmonary lesions may calcify
• May disseminate in AIDS and immunocompromised
(meningitis, mucocutaneous lesions)
• Has a tendency to disseminate in third trimester of pregnancy
(arthroconidia) • Dimorphic fungus
Blastomyces dermatitidis Blastomycosis • Environmental form: hyphae with conidia
• Tissue form: broad-based budding yeast
Definition of abbreviations: RES, reticuloendothelial. • Pulmonary disease
• Disseminated disease
138
►►Opportunistic Fungi
Aspergillus fumigatus • Allergic bronchopulmonary • Dichotomously branching GENERAL PRINCIPLES │ 5. Microbiology
aspergillosis/asthma, cystic • Generally acute angles
fibrosis • Septate
• Compost pits, moldy marijuana
• Fungus ball: free in preformed • May cause disease in immunocompromised patients
lung cavities
Treatment: itraconazole, amphotericin B; depends on severity of
• Invasive aspergillosis/severe infection
neutropenia, CGD, CF, burns
Diagnosis:
− Invades tissues, causing • KOH: pseudohyphae, true hyphae, budding yeasts
infarcts and hemorrhage • Septicemia: culture lab identification: biochemical tests/formation of
− Nasal colonization germ tubes
→pneumonia or meningitis Treatment:
• Topical imidazoles or oral imidazoles; nystatin
− Cellulitis/in burn patients; • Disseminated: amphotericin B or fluconazole
may also disseminate
• Encapsulated yeast (monomorphic)
Candida albicans • Involvement of the oral cavity • Environmental source: Soil enriched with pigeon droppings
(and other spp. of and digestive tract • Diagnosis of meningitis: CSF
Candida) − Detect capsular antigen in CSF (by latex particle agglutination or
• Septicemia, endocarditis in IV
drug abusers counter immunoelectrophoresis)
− I ndia ink mount (misses 50%) of CSF sediment to find budding
• Mucocutaneous candidiasis
yeasts with capsular “halos”
Cryptococcus • Meningitis/Hodgkin, AIDS (the − Cultures (urease ⊕ yeast)
neoformans dominant meningitis) • Treatment: amphotericin B plus flucytosine until afebrile and culture – ,
• Acute pulmonary (usually then fluconazole
asymptomatic)/pigeon breeders
• Nonseptate, filamentous fungi
Mucor, Rhizopus, Rhinocerebral infection • Characterized by paranasal swelling, necrotic tissues, hemorrhagic
Absidia (mucormycosis) caused
(Zygomycophyta by Mucor (or other exudates from nose and eyes, mental lethargy
family) Zygomycophyta) • Occurs in ketoacidotic diabetic patients and leukemic patients
• These fungi penetrate without respect to anatomic barriers,
Pneumocystis jiroveci Pneumonia in AIDS patients,
(formerly carinii) malnourished babies, progressing rapidly from sinuses into brain tissue
premature neonates, other • Diagnosis: KOH of tissue; broad, ribbon-like nonseptate hyphae with
immunocompromised
about 90° angles on branches
• Treatment: débride necrotic tissue and start amphotericin B fast; high
fatality rate because of rapid growth and invasion
• An exudate with foamy or honeycomb appearance on H & E stain
• Patchy infiltrative (ground-glass appearance) on x-ray
• Diagnosis: silver-staining cysts in bronchial alveolar lavage fluids or
biopsy
• Treatment: trimethoprim/sulfamethoxazole, pentamidine
Definition of abbreviations: CF, cystic fibrosis; CSF, cerebrospinal fluid; CGD, chronic granulomatous disease; KOH, potassium hydroxide.
139
►►Antifungal Agents
GENERAL PRINCIPLES │ 5. Microbiology Because fungi are eukaryotic, finding selectively toxic antifungal agents is difficult. Consequently, treating fungal infections poses a clinical
challenge, especially in immunocompromised patients. Fungal cell membranes contain ergosterol, a sterol not found in mammalian tissue.
Thus, this difference provides the basis for most systemically administered antifungal agents.
Class/Agent Mechanism of Action Spectrum/Clinical Use Mechanism(s) Toxicity/Notes
of Resistance
Agents for Systemic Infections
Amphotericin B Binds ergosterol, Widest antifungal spectrum: Very uncommon; ↓ • Fever and chills
causing formation of Aspergillus or structurally altered (“cytokine storm”)
artificial pores, thus Coccidioides ergosterol
altering membrane Blastomyces • Nephrotoxicity limits
permeability, killing the Candida albicans dosing (cumulative over
cell Cryptococcus lifetime)
Histoplasma
Mucor • Reversible anemia
Sporothrix schenckii (secondary to ↓
erythropoietin)
• Arrhythmias
• IV only
Flucytosine Permease allows entry, Narrow spectrum: Rapid if used as a • Reversible bone
deaminated to 5-FU, single agent; ↓ activity marrow suppression
then converted to Cryptococcus of fungal permeases
5-FdUMP (thymidylate and deaminases • Alopecia
synthase inhibitor) C andida albicans
(systemic) • Typically combined
with amphotericin B or
fluconazole
Azoles: Inhibit synthesis of Varies: ↓ sensitivity of target • Vomiting and diarrhea
fluconazole, ergosterol, leading Candida enzymes • Skin rash
itraconazole, to altered membrane Coccidioides • Hepatotoxicity (rare)
voriconazole, permeability Cryptococcus • Gynecomastia
ketoconazole Aspergillus • ↓ P450
Histoplasma
Echinocandin/ Inhibits synthesis Candida • Not very toxic
caspofungin of β-1,2 glycan, a Aspergillus
component of fungal • Headache
cell walls
• Infusion-related
reactions
Systemic Agents for Superficial Infections
Griseofulvin • Uptake by energy- • Dermatophytes of the ↓ in transport/uptake • Confusion and vertigo
dependent transport hair and scalp • Headache
• Blurred vision
• Interferes with • Accumulates in keratin • Nausea/vomiting
microtubule formation • ↑ P450
in dermatophytes • GI irritation
• Disulfiram-like
• May inhibit
polymerization of reaction with ethanol
nucleic acids
Terbinafine Inhibits squalene Accumulates in keratin, • GI irritation
epoxidase (for sterol used in onychomycosis • Rash
biosynthesis) • Headache
• Taste disturbance
Azoles (see above)
Topical Antifungals ✝
Nystatin Disrupts membrane by Candida, especially in oral Same as amphotericin • Contact dermatitis
binding ergosterol candidiasis (thrush) B
• Stevens-Johnson
syndrome
✝ Topical azoles, such as miconazole and clotrimazole are also widely used.
140
Embryology Chapter 6
General Principles of Embyrology
Early Embryology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142–144
Germ-Layer Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
Placenta . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Twinning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Teratogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
141
General Principles of Embryology
GENERAL PRINCIPLES │ 6. Embryology ►►Early Embryology
Week 1
Cleavage:mitosis Fertilization occurs in the
ampulla of the uterine tube
Day 2 Day 3 when the male and female
2-cell Blastula 4-cell Blastula pronuclei fuse to form a
zygote. At fertilization, the
Day 4 Embryoblast secondary oocyte rapidly
Morula (Embryo) completes meiosis II.
(46, 2N) Zygote Trophoblast During the first 4 to 5 days
Day 1 (Placenta) of the first week, the zygote
undergoes rapid mitotic
Day 5 division (cleavage) in the
Blastocyst oviduct to form a blastula,
consisting of increasingly
Fertilization Day 6 (Implantation smaller blastomeres. This
begins) becomes the morula (32-cell
stage).
Zona Corona Ovary Cytotrophoblast
pellcida radiata cells Blastocyst cavity A blastocyst forms as fluid
Ampulla Embryoblast develops in the morula. The
Secondary oocyte of oviduct blastocyst consists of an
arrested in metaphase Syncytiotrophoblast inner cell mass known as
of meiosis II the embryoblast, and the
outer cell mass known as the
trophoblast becomes the
placenta.
At the end of the first week,
the trophoblast differentiates
into the cytotrophoblast
and syncytiotrophoblast
and then implantation begins.
Implantation usually occurs in
the posterior superior wall
of the uterus.
FigCurlienIiIc-2a-l1C. Worereekla1tion: Ectopic Pregnancy
Tubal The most common form of ectopic pregnancy
Usually occurs when the blastocyst implants within the ampulla of the uterine tube because of delayed transport
Risk factors: endometriosis, pelvic inflammatory disease (PID), tubular pelvic surgery, or exposure to diethylstilbestrol
(DES)
Clinical signs: abnormal or brisk uterine bleeding, sudden onset of abdominal pain that may be confused with
appendicitis, missed menstrual period (e.g., LMP 60 days ago), positive human chorionic gonadotropin (hCG) test,
culdocentesis showing intraperitoneal blood, positive sonogram
Abdominal Most commonly occurs in the rectouterine pouch (pouch of Douglas)
(Continued)
142
►►Early Embryology (Cont’d.)
Week 2
Hypoblast Bilaminar disk Lacuna spaces The embryoblast differentiates into GENERAL PRINCIPLES │ 6. Embryology
Epiblast the epiblast and hypoblast, form-
ing a bilaminar embryonic disk.
Endometrial The epiblast forms the amniot-
blood vessel ic cavity, and hypoblast cells
migrate from the primary yolk
Endometrial sac.
gland
The prechordal plate, formed from
fusion of epiblast and hypoblast
cells, is the site of the future mouth.
Prechordal Syncytiotrophoblast Extraembryonic mesoderm
plate • Implantation is derived from the epiblast.
• hCG Extraembryonic somatic
Chorionic cavity mesoderm lines the cytotro-
Yolk sac Connecting stalk phoblast, forms the connecting
stalk, and covers the amnion.
Amniotic cavity Primary villi Extraembryonic visceral
mesoderm covers the yolk sac.
The connecting stalk suspends
the conceptus within the chorionic
cavity. The wall of the chorionic
cavity is called the chorion, con-
sisting of extraembryonic somatic
mesoderm, the cytotrophoblast,
and the syncytiotrophoblast.
Chorion
Extraembryonic
mesoderm
Cytotrophoblast
• Primary villi
Figure II-3-1. WeeCkli2nical Correlation
Human chorionic gonadotropin (hCG) is a glycoprotein produced by the syncytiotrophoblast. It stimulates progesterone production
by the corpus luteum. hCG can be assayed in maternal blood or urine and is the basis for early pregnancy testing. hCG is detectable
throughout pregnancy. Low hCG levels may predict a spontaneous abortion or ectopic pregnancy. High hCG levels may predict a multiple
pregnancy, hydatidiform mole, or gestational trophoblastic disease.
(Continued)
143
►►Early Embryology (Cont’d.)
Weeks 3 Through 8
GENERAL PRINCIPLES │ 6. Embryology A Cranial Third week: gastrulation and early development
of nervous and cardiovascular systems; corre-
Prechordal sponds to first missed period
plate
Gastrulationa process that produces the
Primitive node three primary germ layers: ectoderm, meso-
Primitive pit
derm, and endoderm; begins with the formation
Primitive streak
of the primitive streak within the epiblast
B Ectoderm → neuroectoderm and neural crest
Cranial Primitive node & streak cells
Cloacal Epiblast (Ectoderm) Mesoderm → paraxial mesoderm (35 pairs of
membrane Amnion somites), intermediate mesoderm, and lateral
mesoderm
Caudal Notochord All major organ systems begin to develop during
Yolk sac the embryonic period (Weeks 3–8). By the end
of this period, the embryo begins to look human.
Mesoderm Hypoblast
Endoderm
Figure II-4-1. Week 3 Clinical Correlation
Sacrococcygeal teratoma: a tumor that arises from remnants of the primitive streak; often contains various types of tissue (bone, nerve,
hair, etc.).
Chordoma: a tumor that arises from remnants of the notochord, found either intracranially or in the sacral region
Caudal dysplasia (sirenomelia): a constellation of syndromes ranging from minor lesions of the lower vertebrae to complete fusion of
lower limbs. Occurs as a result of abnormal gastrulation, in which migration of mesoderm is disturbed. Associated with VATER (vertebral
defects, anal atresia, tracheoesophageal fistula, and renal defects) or VACTERL (vertebral defects, anal atresia, cardiovascular defects,
tracheoesophageal fistula, renal defects, and upper limb defects)
Hydatidiform mole: results from the partial or complete replacement of the trophoblast by dilated villi
• In a complete mole, there is no embryo; a haploid sperm fertilizes a blighted ovum and reduplicates so that the karyotype is 46,XX,
with all chromosomes of paternal origin. In a partial mole, there is a haploid set of maternal chromosomes and usually two sets of
paternal chromosomes so that the typical karyotype is 69,XXY.
• Molar pregnancies have high levels of hCG, and 20% develop into a malignant trophoblastic disease, including
choriocarcinoma.
►►Germ-Layer Derivatives
Ectoderm
Surface ectoderm Epidermis, hair, nails, inner and external ear, tooth enamel, lens of eye, anterior pituitary (from Rathke pouch),
major salivary, sweat, and mammary glands; epithelial lining of nasal and oral cavities and ear
Neuroectoderm CNS (brain and spinal cord), retina and optic nerve, pineal gland, neurohypophysis, astrocytes, oligodendrocytes,
ependymal cells
Neural crest Adrenal medulla, ganglia (sensory, autonomic), melanocytes, Schwann cells, meninges (pia, arachnoid),
pharyngeal arch cartilage, bones of the skull, odontoblasts, parafollicular (C) cells, laryngeal cartilage,
aorticopulmonary septum, endocardial cushions (abnormal development can lead to many congenital defects)
Mesoderm Muscle (smooth, cardiac, skeletal), connective tissue, serous membranes, bone and cartilage, blood and blood
vessels, lymphatics, cardiovascular organs, adrenal cortex, gonads and internal reproductive organs, spleen,
kidney and ureter, dura mater
Endoderm Epithelial parts: GI tract, tonsils, thymus, pharynx, larynx, trachea, bronchi, lungs, urinary bladder, urethra,
tympanic cavity, auditory tube and other pharyngeal pouches
Parenchyma: liver, pancreas, tonsils, thyroid, parathyroids, glands of GI tract, submandibular and sublingual glands
144
►►Placenta GENERAL PRINCIPLES │ 6. Embryology
The placenta permits exchange of nutrients and waste products between maternal and fetal circulations.
Umbilical arteries (2)
Umbilical vein (1) Maternal
Syncytiotrophoblast blood
Chorionic
plate
Villus
Fetal
Maternal Decidua Myometrium
basalis Perimetrium
Uterine vein
Uterine artery
Fetal component Chorionic plate and villi
Syncytiotrophoblast: outer layer of chorionic villi; secretes hCG
Maternal component Cytotrophoblast: inner layer of chorionic villi
Placental barrier
Umbilical cord Decidua basalis: Maternal blood vessels from the decidua conduct blood into the intervillous spaces of
the placenta, where floating villi are present
The syncytiotrophoblast, cytotrophoblast, basement membrane, fetal capillary endothelium separate the
maternal and fetal blood
1 umbilical vein supplies oxygenated blood from the placenta to the fetus
2 umbilical arteries carries deoxygenated blood back from the fetus to the placenta
Urachus: Removes nitrogenous waste from the fetal bladder
►►Twinning
The type of twinning depends on the point in time in which cleavage occurs. If the twinning occurs very early
on (before the chorion forms), two separate chorions will form (dichorionic). All other possible types of twins
are monochorionic because the chorion has already formed. Fraternal twins are dizygotic and identical twins
are monozygotic.
Placental morphology Time of cleavage Type of twin
Dichorionic diamniotic Very early (Days 1–3) Fraternal or identical
Monochorionic diamniotic Early (Days 4–8) Identical
Monochorionic monoamniotic Later (Days 8–13): identical Identical, conjoined
Even later (Days 13–15): conjoined
145
GENERAL PRINCIPLES │ 6. Embryology ►►Teratogens Renal damage
CN VIII toxicity
ACE inhibitors; ARBS Masculinization of female fetus
Aminoglycosides Neural tube defects (carbamazepine, valproic acid), phenytoin (fetal
Androgens
Anticonvulsants hydantoin syndrome); multiple congenital defects
Congenital goiter, hypothyroidism
Antithyroid drugs Vaginal clear cell adenocarcinoma; vaginal adenosis
Diethylstilbestrol (DES) Fetal alcohol syndrome (e.g., growth retardation, facial abnormalities,
Ethanol
microcephaly, cardiac defects)
Folate antagonists Multiple congenital anomalies
Lithium Ebstein anomaly
Radiation Multiple abnormalities
Tetracyclines Discoloration of teeth
Thalidomide Phocomelia (limb reduction defects)
Warfarin Bone and cartilage abnormalities, hemorrhage, etc.
Vitamin A excess; vitamin A Multiple abnormalities, e.g., cleft palate, cardiac abnormalities,
derivatives mental retardation
146
Physiology Chapter 7
Physiologic Terminology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
Transport . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
Diffusion Kinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
Fluid Volume Compartments and Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
Summary of Volume and Osmolarity Changes of Body Fluids . . . . . . . . . . . . . . 150
Membrane Potentials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
Action Potential . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
147
►►Physiologic Terminology
Equilibrium Equilibrium occurs when the balance of opposing forces has reached the lowest free energy state, and as a result,
a given variable has reached a constant value.
GENERAL PRINCIPLES │ 7. Physiology
Steady state Steady state is a condition in which a variable is maintained within narrow limits by regulating an opposing activity.
This process requires energy.
Negative This is a common system that acts to oppose changes in the internal environment. Negative feedback systems
feedback promote stability and act to restore steady-state function after a perturbation.
Positive This is a less common system (also called a vicious cycle) that acts to magnify a change in the internal environment;
feedback the initial change in a system is increased as a result of feedback activity. In a viable organism, any positive feedback
system is ultimately overridden by one or more negative feedback systems.
Negative Feedback Example Positive Feedback Example
Follicular Phase Pre-ovulatory Phase
Gonadotropin-releasing hormone Gonadotropin-releasing hormone
Luteinizing hormone Luteinizing hormone
Estradiol Estradiol
The figures above show the negative feedback relationship between estrogens and the gonadotropins that dominates during the follicular
phase, which transforms into a positive feedback relationship, producing the LH surge prior to ovulation. Solid arrows show direct
relationships (stimulation) and dashed arrows show inverse relationships (inhibition).
►►Transport Energy Source Example Other Characteristics Clinical Correlation
Type of Transport
Simple diffusion Passive Pulmonary gases Pulmonary edema decreases
diffusion
Carrier-mediated or Passive Glucose uptake by • Insulin controls carrier Insulin-dependent glucose
facilitated diffusion muscle population uptake impaired in diabetes
mellitus
Primary active Direct use of ATP Na+/K+-ATPase • Chemical specificity
transport Ca2+-ATPase Antiport (countertransport) Inhibition by cardiac glycosides
Regulates cellular Ca2+
Secondary active Electrochemical Na+-glucose in Deficiency causes
transport gradient for kidney Symport (cotransport) neuromuscular disorders
sodium is most
common driving Na+-H+ exchange Antiport (countertransport) Osmotic diuresis results when
force transporters saturated
Renal tubular acidosis
Key Points
• Passive processes are directly related to concentration gradients.
• Active processes create or increase a concentration gradient and thus depend upon metabolic energy.
• Both carrier-mediated facilitated diffusion and active transport can be saturated; maximum transport rate depends on population and
activity of transport molecules.
• Primary active transport proteins have an ATPase as part of their structure.
• Most secondary active transport depends upon the electrochemical gradient of sodium ions, which in turn depends on the activity of
the primary active transporter, sodium-potassium ATPase.
148
►►Diffusion Kinetics
Simple The rate is estimated by Fick’s law of diffusion: J = −DA(∆C/∆X) GENERAL PRINCIPLES │ 7. Physiology
diffusion J = net flux, D = diffusion coefficient, A = surface area, ∆C = concentration or pressure gradient, ∆X = diffusion distance
Changes in surface area or diffusion distance are most important in disease states (e.g., the decrease in surface area
caused by destruction of alveoli in emphysema or the decreased diffusion of oxygen during pulmonary edema related
to increased diffusion distance).
Carrier- Influx active transport
mediated Simple diffusion Extracellular
transport
Concentration
Intracellular, Facilitated diffusion increases
transport rate above that capable
Facilitated diffusion Intracellular, passive with simple diffusion, but has
saturation kinetics (left).
Extracellular concentration
Assumption: intracellular concentration Active transport can produce
is negligible a concentration gradient, and
passive processes will lead to
an equilibrium state (right).
Time
Assumption: extracellular concentration
does not change
►►Fluid Volume Compartments and Distribution
% of Body Fraction of Markers Used to Primary
Weight Cations
TBW Measure Volume Primary Anions
Total body water (TBW) 60 1.0 Tritiated H2O
Intracellular fluid volume (ICF) 40 D2O, antipyrine
²⁄³ TBW – ECF* K+ Organic phosphates;
protein
Extracellular fluid volume (ECF) 20 ¹⁄³ Inulin Na+ Cl−
Plasma 5 ¹⁄¹E² C(¼F)of Mannitol HCO3−
RISA Na+ Cl−
Evans blue HCO3−
Plasma proteins
Interstitial fluid 15 ¼ (¾ of ECF-plasma volume* Na+ Cl−
HCO3−
ECF)
Principles of Fluid Distribution
1. Osmolarity of the ICF and ECF are equal.
2. Intracellular volume changes only when extracellular osmolarity changes.
3. All substances enter or leave the body by passing through the extracellular compartment.
Measurement of Fluid Volumes
Volume = Mass Example: 100 mg of inulin is infused. After equilibration, its concentration = 0.01 mg/mL.
Concentration What is patient’s ECF volume?
Answer: ECF = 100 mg/0.01 mg/mL = 10,000 mL, or 10 L
Osmolarity and Mass
1. P lasma osmolarity in mOsm/L can be quickly estimated as twice the plasma sodium concentration in mmol/L. More rigorously, plasma
osmolarity (mOsm/L) = (2 × serum sodium [mEq/L]) + (BUN [mg/dL]/2.8) + (glucose [mg/dL]/18).
2. Mass of solutes in the TBW, ICF, or ECF in mOsm is calculated by the relevant volume multiplied by the osmolarity.
Definition of abbreviation: RISA, radio-iodinated serum albumin.
*Indirect measurement
149
►►Summary of Volume and Osmolarity Changes of Body Fluids
GENERAL PRINCIPLES │ 7. Physiology Body osmolarity and intracellular and extracellular fluid volumes volume Concentration of Solute volume
change in clinically relevant situations. The Darrow-Yannet
diagram (right) represents this information. The y-axis is solute ICF ECF
concentration or osmolarity. The x-axis is the volume of ICF and o
ECF. The solid line represents the control state, and the dashed
line represents changes in volume or osmolarity. In this example, ICF Volume D-Y Diagram
osmolarity ↓, ICF volume ↑, and ECF volume ↓.
Type Examples ECF Body
Volume Osmolarity
Isosmotic volume Diarrhea, hemorrhage, ↓ No change No change
contraction vomiting
(loss of isotonic fluid)
Isosmotic volume Isotonic saline infusion ↑ No change No change
expansion
(gain of isotonic fluid)
Hyperosmotic volume Dehydration, diabetes ↓ ↑ ↓
contraction insipidus
(loss of water)
Hyperosmotic volume Excessive NaCl intake, ↑ ↑ ↓
expansion hypertonic mannitol, ↓ ↓ ↑
(gain of NaCl) chronic aldosterone ↑
excess
Hyposmotic volume
contraction Adrenal insufficiency
(loss of NaCl)
Hyposmotic volume SIADH, water intoxication ↑ ↓
expansion
(gain of water)
Definiton of abbreviation: SIADH, syndrome of inappropriate antidiuretic hormone.
150
►►Membrane Potentials
Equilibrium Amount of voltage needed to balance the chemical force due to its concentration gradient GENERAL PRINCIPLES │ 7. Physiology
potential The Nernst equation can determine this. For a monovalent cation:
Ex = 60 mV log10 [X]o ; Ex = equilibrium potential, [X] = ion concentration (out and in), Z = charge
Z [X]i
(Na+ = 1, Cl– = –1, Ca2+ = 2)
Resting membrane • RM is the potential difference across a cell membrane in millivolts (mV); −70 mV is typical.
(RM) potential • RM occurs because of an unequal distribution of ions between the ICF and ECF and the selective
permeability of the membrane to ions. Proteins (anions) in cells that do not diffuse help establish the
electrical potential across the membrane.
• The relative effect of an ion on the membrane potential is in proportion to the conductance or permeability of
that ion. The greater the conductance, the closer the membrane will approach the equilibrium potential of
that ion.
• The resting potential of cells is negative inside. Hyperpolarization occurs when the membrane potential
becomes more negative. Depolarization occurs when the membrane potential becomes less negative or
even positive.
Chord Em = (gK/Σg × EK) + (gNa/Σg × ENa) + (gCl/Σg × ECl)
conductance Em = membrane potential in mV; g = conductance of individual ion; Σg = total conductance of cell membrane; E
equation = equilibrium potential of individual ion from Nernst equation
• Used to calculate membrane potential; useful to evaluate effects of ion conductance and concentrations;
explains action potential, synaptic potentials, and electrolyte disorders
Properties of Ion Extracellular (mM) Intracellular (mM) Equilibrium Conductance
ions in a typical Na+ 150.0 15.0 Potential (mV) Very low
neuron
+60
K+ 5.5 150.0 −90 High
Cl− 125.0 9.0 −70 High
• Because potassium and chloride have a high conductance, their equilibrium potentials dominate
the membrane potential, so the inside of the cell is negative.
• C hanges in EC K+ can produce large changes in the membrane potential:
↑ EC K+ → depolarization; ↓ EC K+ → hyperpolarization.
• Changes in EC Na+ have little effect on membrane potential, but an increase in Na+ conductance →
depolarization.
Definition of abbreviation: EC, extracellular.
151
►►Action Potential
GENERAL PRINCIPLES │ 7. Physiology Absolute Relative
refractory refractory
period period
60 mV Sodium equilibrium potential
0 mV Action potential
Sodium conductance
Potassium conductance
– 70 mV Resting equilibrium potential
– 90 mV Potassium equilibrium potential
Time
The action potentials (AP) of excitable cells involve the opening and closing of voltage-gated channels for sodium, potassium, and in
some cells, calcium. The figure above shows a neuronal AP. The opening of a channel increases conductance.
Steps are shown below.
• Inward currents depolarize the membrane potential to threshold.
• Voltage-gated Na+ channels open, causing an inward Na+ current. The membrane potential approaches the Na+ equilibrium
potential. These channels can be blocked by tetrodotoxin.
• These Na+ channels close rapidly (inactivation), even though the membrane is still depolarized.
• Depolarization slowly opens K+ channels, increasing K+ conductance (outward current), leading to repolarization.
• Absolute refractory period: An AP cannot be elicited because Na+ channels are closed.
• Relative refractory period: Only a greater than normal stimulus can produce an AP because the K+ conductance is still higher than
at rest.
• The Na+-K+ pump restores ion concentrations. It is electrogenic (3 Na+ pumped out for every 2 K+ pumped in).
Clinical Correlations
Calcium has a low resting conductance and does not contribute to the resting potential. It has a very positive equilibrium potential, so
when conductance increases (e.g., cardiac and smooth muscle cells), depolarization occurs. Calcium concentration affects the action
potentials and force of contraction of cardiac and smooth muscle.
Hypercalcemia stabilizes excitable membranes, leading to flaccid paralysis of skeletal muscle. Hypocalcemia destabilizes membranes,
leading to spontaneous action potentials and spasms.
Abnormal increases and decreases of extracellular potassium have severe consequences for cardiac conduction and rhythm.
Renal and gastrointestinal disorders are likely to cause abnormalities of electrolytes and alteration of resting potentials and action
potentials.
152
Pathology Chapter 8
Cellular Injury and Adaptation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
Direct and Indirect Results of Reversible Cell Injury . . . . . . . . . . . . . . . . . . . . . . . 155
As the Degree of Cellular Injury Worsens... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
Irreversible Injury and Cell Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
Apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
Adaptive Cellular Responses to Injury (Potentially Reversible) . . . . . . . . . . . . . . 156
Regeneration and Repair
Capacity of Cells to Regenerate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
Wound Healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
Connective Tissue Components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
Growth Factors and Cytokines Involved in Growth Repair . . . . . . . . . . . . . . . . . 157
Connective Tissue Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
Staining Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
Amyloidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
Neoplasia
Basic Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
Selected Risk Factors for Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
Mechanisms of Carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160–161
Oncogenic Viruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
Serum Tumor Markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
Paraneoplastic Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
Grading and Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
Cancer Incidence and Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
153
Cellular Injury and Adaptation
GENERAL PRINCIPLES │ 8. Pathology Changing conditions in the cell’s environment can produce changes Homeostatic cell
from adaptation to injury or even cell death. The cellular response to Metabolic changes
injury depends on the type, duration, and severity of injury, the type of
cell injured, metabolic state, and ability to adapt. Ischemia
Toxins, etc.
Adaptation Injury
Reversible Irreversible
changes changes
Causes Examples
Hypoxia (most common) • Ischemia (e.g., arteriosclerosis, thromboembolus)
• Cardiopulmonary failure
Infections • Severe anemia
Immunologic reactions
Congenital/metabolic disorders Viruses, bacteria, parasites, rickettsiae, fungi, prions
Chemical injury
• Hypersensitivity reactions
Physical injury • Autoimmune
Nutritional or vitamin imbalance
• Inborn errors of metabolism (e.g., phenylketonuria, galactosemia, glycogen storage
diseases)
• Drugs (e.g., therapeutic, drugs of abuse)
• Poisons
• Pollution
• Occupational exposure (e.g., CCl4, CO, asbestos)
Trauma, burns, frostbite, radiation
• Inadequate calorie/protein intake (e.g., marasmus, kwashiorkor, anorexia nervosa)
• Excess caloric intake (e.g., obesity, atherosclerosis)
• Vitamin deficiencies
• Hypervitaminosis
Important Mechanisms of Cell Injury Protective Factors Against Free Radicals
• Oxygen-free radicals (superoxide [O2.–], hydroxyl radical [OH.], 1. Antioxidants—vitamins A, E, and C
hydrogen peroxide [H2O2]) damage DNA, proteins, lipid mem- 2. Superoxide dismutase—superoxide → hydrogen peroxide
branes, and circulating lipids (LDL) by 3. Glutathione peroxidase—hydroxyl ions or hydrogen
peroxidation
peroxide → water
• Decreased oxidative phosphorylation 4. Catalase—hydrogen peroxide → oxygen and water
• ATP depletion
• Increased cell-membrane permeability
• Influx of calcium—activates a wide spectrum of enzymes: prote-
ases, ATPases, phospholipases, endonucleases
• Mitochondrial dysfunction, formation of mitochondrial
permeability transition (MPT) channels
• Release of cytochrome c is a trigger for apoptosis
154
►►Direct and Indirect Results of Reversible Cell Injury
Direct Result Consequences Pathophysiologic Correlates
Decreased synthesis of ATP by oxi- Decreased function of Na+/K+ ATPase → Cellular swelling (hydropic swelling), swelling GENERAL PRINCIPLES │ 8. Pathology
dative phosphorylation influx of Na+ and water, efflux of K+, and swell- of endoplasmic reticulum, membrane blebs,
ing of the ER myelin figures
Increased glycolysis → Increased lactic acid production → decreased Tissue acidosis
glycogen depletion intracellular pH
Ribosomes detach from rough ER Decreased protein synthesis Lipid deposition (fatty change)
►►As the Degree of Cellular Injury Worsens . . .
Severe plasma membrane Massive influx of calcium, efflux of intracellular Markers of cellular damage detectable in
damage enzymes and proteins into the circulation serum (LDH, CK, ALT, AST, troponin, etc.)
Calcium influx into mitochondria Irreparable damage to oxidative Mitochondrial densities
phosphorylation
Lysosomal contents leak out Lysosomal hydrolases are activated Autolysis, heterolysis, nuclear changes (pykno-
intracellularly sis, karyorrhexis, karyolysis)
►►Irreversible Injury and Cell Death
Morphologic Pattern Characteristics
Coagulative necrosis Most common (e.g., heart, liver, kidney)
Proteins denatured, nucleus is lost, but cellular shape is maintained
Liquefactive necrosis Abscesses, brain infarcts, pancreatic necrosis
Cellular destruction by hydrolytic enzymes
Caseous necrosis Seen in tuberculosis
Combination of coagulation and liquefaction necrosis → soft, friable, and “cottage-cheese–like” appearance
Fat necrosis Caused by the action of lipases on fatty tissue (e.g., with pancreatic damage)
Chalky white appearance
Fibrinoid necrosis Eosinophilic homogeneous appearance—resembles fibrin
Gangrenous necrosis Common sites: lower limbs, gallbladder, GI tract, and testes
Dry gangrene—coagulative necrosis
Wet gangrene—liquefactive necrosis
Apoptosis A specialized form of programmed cell death, an active process under genetic control
Often affects only single cells or small groups of cells
Mediated by a cascade of caspases (digest nuclear and cytoskeletal proteins and activate endonucleases)
Myocardial ischemia is a good example of cellular injury and death.
Myocardial Ischemia
Decreased Oxidative Phosphorylation
Na+ K+ ATPase pump Glycolysis Ribosomal Severe Membrane
Detachment Damage
Influx of Na+ Glycogen Lactic Acid Protein Influx of Ca2+ Cytoplasmic
Efflux of K+ Synthesis Enzyme Leak
Out of Cell
(i.e., CK-MB)
Cell Swelling pH
Endoplasmic Reticulum Swelling
Loss of Microvilli
Membrane Blebs
155
►►Apoptosis
Morphology Stimuli for Genetic Physiologic Examples Pathologic Examples
Apoptosis Regulation
GENERAL PRINCIPLES │ 8. Pathology • Cells shrink, • Cell injury and • bcl-2 (inhibits • Embryogenesis— • Viral hepatitis
cytoplasm is dense DNA damage apoptosis) organogenesis and (Councilman body)
and eosinophilic development
• Lack of hormones, • p-53 (stimulates • Graft versus host
• Nuclear chromatin cytokines, or apoptosis) • Hormone-dependent disease
condenses, then frag- growth factors apoptosis (menstrual
ments cycle) • Cystic fibrosis (CF)—duct
• Receptor-ligand obstruction and pancre-
• Cell membrane blebs signals: • Selective death of atic atrophy
• Cell fragments lymphocytes in thymus
– Fas binding to
(apoptotic bodies) Fas ligand
are phagocytized by
adjacent cells or mac- – Tumor necrosis
rophages factor (TNF)
• Lack of inflammatory binding to TNF
response receptor 1
(TNFR1)
►►Adaptive Cellular Responses to Injury (Potentially Reversible)
Types Definitions Causes
Atrophy Decrease in cell size and functional ability. Cells shrink; • Deceased workload/disuse
lipofuscin granules can be seen microscopically. EM— • Ischemia
autophagosomes • Lack of hormonal or neural stimulation
• Malnutrition
• Aging
Hypertrophy An increase in cell size and functional ability mediated by • Increased mechanical demand, e.g., striated
growth factors, cytokines, and other trophic stimuli, leading muscle of weight lifters, cardiac muscle in
to increased expression of genes and increased protein syn- hypertension
thesis. May coexist with hyperplasia.
• Increased endocrine stimulation, e.g., puberty,
pregnancy, lactation
Hyperplasia An increase in the number of cells in a tissue or organ, Physiologic causes:
mediated by growth factors, cytokines, and other trophic
stimuli. Increased expression of growth-promoting genes • Compensatory (e.g., after partial hepatectomy)
(proto-oncogenes), increased DNA synthesis, and cell divi-
sion • Hormonal stimulation (e.g., breast
development at puberty)
• Antigenic stimulation (e.g., lymphoid
hyperplasia)
Pathologic causes:
• E ndometrial hyperplasia
• Prostatic hyperplasia of aging
Metaplasia A reversible change of one cell type to another Irritation
Dysplasia An abnormal proliferation of cells characterized by Similar to stimuli that produce cancer (e.g., HPV,
changes in cell size, shape, and loss of cellular organization; esophageal reflux)
premalignant, e.g., cervical dysplasia
156
Regeneration and Repair
Wound healing involves regeneration of cells in a damaged tissue, along with repair of the connective tissue matrix. GENERAL PRINCIPLES │ 8. Pathology
►►Capacity of Cells to Regenerate
Cell Type Properties Examples
Labile Regenerate throughout life Skin and mucosal lining cells
Hematopoietic cells
Stable Replicate at a low level throughout life Stem cells
Permanent Have the capacity to divide if stimulated by some initiating
event Hepatocytes
Proximal tubule cells
Cannot replicate Endothelium
Neurons and cardiac muscle
Growth Factors and Cytokines ►►Wound Healing
Involved in Growth Repair
Primary Union (healing by first intention)
• Transforming growth factor α (TGF-α)
• Platelet-derived growth factor (PDGF) Occurs with clean wounds when there has been
• Fibroblast growth factor (FGF) little tissue damage and wound edges are closely
• Vascular endothelial growth factor (VEGF) approximated, e.g., a surgical incision
• Epidermal growth factor (EGF)
• Tumor necrosis factor α (TNF-α) and IL-1 Secondary Union (healing by second intention)
Occurs in wounds that have large tissue defects (the
►►C onnective Tissue two skin edges are not in contact):
Components • Granulation tissue fills in the defects
• O ften accompanied by significant wound
Collagen production requires vitamin C
(wound healing impaired in scurvy) and copper. contraction; may produce large residual scar
Different types of collagen are found in different Keloids
body sites.
• Type I collagen is the most common form. Occur as result of excessive scar collagen deposition/
• Type II collagen is found in cartilage. hypertrophy, especially in dark-skinned people
• T ype III collagen is an immature form found
Connective Tissue Diseases
in granulation tissue. Scurvy
• T ype IV collage is found in basement
Vitamin C deficiency first affecting collagen with highest
membranes. hydroxyproline content, such as that found in blood
vessels. Thus, an early symptom is bleeding gums.
Other extracellular matrix components include:
– adhesion molecules Ehlers-Danlos (ED) Syndrome
– proteoglycans Defect in collagen synthesis or structure. There are
– glycosaminoglycans many types. ED type IV is a defect in type III collagen.
Osteogenesis Imperfecta
Defect in collagen type I
157
Staining Methods
GENERAL PRINCIPLES │ 8. Pathology Stain Cell Type/Component
Hematoxylin (stains blue to purple) Nuclei, nucleoli, bacteria, calcium
Eosin (stains pink to red) Cytoplasm, collagen, fibrin, RBCs, thyroid colloid
Prussian blue Iron
Congo red Amyloid
Periodic acid-Schiff (PAS) Glycogen, mucin, mucoprotein, glycoprotein, as well as fungi
Gram stain Microorganisms
Trichrome Collagen
Reticulin Reticular fibers in loose connective tissue
Immunohistochemical (antibody) stains:
• Epithelial cells
• Cytokeratin • Connective tissue
• Vimentin • Muscle
• Desmin • Prostate
• Prostate-specific antigen (PSA) • Neurons, neuronally derived, neural crest−derived growths
• S-100, neuron specific enolase, neurofilament • Glial cells (including astrocytes)
• GFAP • Hairy cell leukemia
• Tartrate-resistant acid phosphatase (TRAP) • Small cell lung cancer, carotid body tumor
• Bombesin
Definition of abbreviations: GFAP, glial fibrillary acidic protein.
Amyloidosis
An accumulation of various insoluble fibrillar in various tissues. It stains with Congo red and shows apple-green birefringence with
polarized light.
Disease Major Fibril Protein Precursor Protein
Primary amyloidosis (e.g., plasma cell disorders) AL Kappa or lambda chains
Secondary amyloidosis (e.g., neoplasia, rheumatoid arthritis, SLE, TB, AA Serum amyloid associated
Crohn disease, osteomyelitis, familial Mediterranean fever) (SAA)
Renal hemodialysis Ab2M b2 microglobin
Senile cerebral amyloidosis Ab b-amyloid precursor protein
Cardiac amyloidosis ATTR Transthyretin
Medullary carcinoma of thyroid A Cal Calcitonin
Type 2 diabetes, pancreatic islet-cell tumors A Amylin Amylin
Definition of abbreviations: ATTR, amyloid transthyretin; SLE, systemic lupus erythematosus; TB, tuberculosis.
158
Neoplasia
Carcinogenesis is a multistep process involving multiple genetic changes from inherited germ-line mutations or acquired mutations, GENERAL PRINCIPLES │ 8. Pathology
leading to monoclonal expansion of a mutated cell.
Progression of epithelial cancer: normal epithelium → atypical hyperplasia → dysplasia → carcinoma in situ → invasion, metastasis
(collagenases, hydrolases aid in penetration of barriers, such as basement membrane)
►►Basic Terms Loss of cell differentiation and tissue organization
Anaplasia
Atypical hyperplasia Increased cell number with morphologic abnormalities
Carcinoma Malignant tumor of epithelium
Carcinoma in situ Malignant tumor of epithelium that does not penetrate basement membrane to underlying tissue
Desmoplasia Excessive fibrous tissue formation in tumor stroma
Dysplasia Abnormal atypical cellular proliferation
Metaplasia Replacement of one type of adult cell or tissue by another (within the same germ cell line) that is not
normally present in that site
Metastasis Secondary, discontinuous malignant growth (spread), such as a lung metastasis of a colon carcinoma
Sarcoma A mesenchymal (nonepithelial) malignant tumor
►►Selected Risk Factors for Cancer
Geographic/Racial Stomach cancer (Japan); hepatocellular carcinoma (Asia)
Occupational/Environmental Aflatoxin: hepatocellular carcinoma Chromium and nickel: bronchogenic
exposures carcinoma
Alkylating agents: leukemia, lymphoma,
other cancers Cigarette smoke: multiple malignancies
CCl4: fatty change and centrilobular
Aromatic “−amines” and “azo−” dyes:
hepatocellular carcinoma necrosis of the liver
Ionizing radiation: thyroid cancer, leukemia
Arsenic: squamous cell carcinomas of Naphthylamine: bladder cancer
skin and lung, angiosarcoma of liver Nitrosamines: gastric cancer
Polycyclic aromatic hydrocarbons:
Asbestos: bronchogenic carcinoma,
mesothelioma bronchogenic carcinoma
Ultraviolet exposure: skin cancers
Benzene: leukemia Vinyl chloride: angiosarcoma of liver
Age Increases risk of most cancers (exceptions: Wilms, etc.)
Hereditary predisposition Familial retinoblastoma; multiple endocrine neoplasia, familial polyposis coli
Acquired risk factors Cervical dysplasia, endometrial hyperplasia, cirrhosis, ulcerative colitis, chronic atrophic
gastritis
159
►►Mechanisms of Carcinogenesis
There are many proposed mechanisms of carcinogenesis. The most important mutations involve growth-promoting genes
(proto-oncogenes), growth-inhibiting tumor suppressor genes, and genes regulating apoptosis.
GENERAL PRINCIPLES │ 8. Pathology Clinically Important Oncogenes
Proto-oncogenes are normal cellular genes involved with growth and cellular differentiation. Oncogenes are derived from
proto-oncogenes by changing the gene sequence (resulting in a new gene product, oncoprotein) or a loss of gene regulation →
overexpression of the normal gene product. Oncogenes lack regulatory control and are overexpressed → unregulated cellular
proliferation.
Oncogene Tumor Gene Product Mechanism of Activation
hst-1/int-2 Growth factor Overexpression
sis Cancer of the stomach, breast, Fibroblast growth factor Overexpression
bladder, and melanoma Overexpression
erb-B1 Astrocytoma Platelet-derived growth factor
Growth factor receptor
SCC of lung Epidermal growth factor receptor
erb-B2 Breast, ovary, lung Epidermal growth factor receptor Amplification
erb-B3 Breast Epidermal growth factor receptor Overexpression
ret MEN II and III, familial Glial neurotrophic factor receptor Point mutation
thyroid (medullary) cancer
abl Signal transduction proteins Translocation t(9;22)
Ki-ras CML, ALL bcr-abl fusion protein with tyrosine Point mutation
c-myc Lung, pancreas, and colon Translocation t(8;14)
L-myc Burkitt lymphoma kinase activity Amplification
N-myc Small cell lung carcinoma GTP-binding protein Amplification
Neuroblastoma Nuclear regulatory protein
bcl-1 Nuclear regulatory protein Translocation t(11;14)
Mantle cell lymphoma Nuclear regulatory protein
Cell-cycle regulatory proteins
Cyclin D1 protein
CDK4 Melanoma, glioblastoma Cyclin-dependent kinase Amplification
multiforme
c-kit Gastrointestinal stromal tumor KIT (also called CD117) is a stem Overexpression or mutation
(GIST) cell factor receptor, a receptor
tyrosine kinase
Definition of abbreviations: ALL, acute lymphocytic leukemia; CML, chronic myelogenous leukemia; MEN, multiple endocrine neoplasia;
SCC, squamous cell carcinoma.
(Continued)
160
►►Mechanisms of Carcinogenesis (Cont’d.) Failure of Apoptosis Is Another
Cause of Cancer
Inactivation of Tumor Suppressor Genes
bcl-2
Tumor suppressor genes encode proteins that regulate and suppress cell GENERAL PRINCIPLES │ 8. Pathology
proliferation by inhibiting progression through the cell cycle. Inactivation of these • Prevents apoptosis
genes → uncontrolled cellular proliferation. • Overexpressed in follicular
Gene Chromosome Tumors lymphomas t(14:18) (chromosome 14
VHL 3p25 Von Hippel-Lindau disease, [immunoglobulin heavy chain gene];
chromosome 18 [bcl-2])
WT-1 11p13 renal cell carcinoma
WT-2 11p15 Wilms tumor bax, bad, bcl-xS, bid
Rb 13q14 Wilms tumor
p53 17p13.1 Retinoblastoma, osteosarcoma • Promote apoptosis
BRCA-1 17q12-21 Lung, breast, colon, etc. • p53 promotes apoptosis in mutated
BRCA-2 13q12-13 Hereditary breast and ovary cancers
APC 5q21 Hereditary breast cancer cells by stimulating bax synthesis;
DCC 18q21 Adenomatous polyps and colon cancer inactivation → failure of apoptosis
NF-1 17q11.2 Colon cancer
NF-2 22q12 Neurofibromas c-myc
p16 9p Acoustic neuromas, meningiomas
DPC4 18q21 Melanoma • Promotes cellular proliferation
Pancreatic cancer • When associated with p53 →
promotes apoptosis; when associated
with bcl-2 → inhibits apoptosis
►►Oncogenic Viruses
Specific virus Human T-cell Hepatitis B Epstein-Barr Human papilloma Human
leukemia virus (HTLV- (HBV) virus (types 16, herpesvirus 8
1)* Hepatitis C Burkitt lymphoma, 18 in genital (HHV-8)
(HCV)* B-cell lymphoma, sites)
nasopharyngeal
Associated Adult T-cell leukemia/ Hepatocellular carcinoma Cervical, Kaposi sarcoma
disease lymphoma carcinoma vulvar, vaginal,
penile, and anal
carcinoma; some
head and neck
cancers
*RNA oncogenic viruses (all other are DNA).
161
►►Serum Tumor Markers
These are usually normal cellular components that are increased in neoplasms but may also be elevated in non-neoplastic conditions.
Can be used for screening, monitoring of treatment efficacy, and detecting recurrence.
GENERAL PRINCIPLES │ 8. Pathology Marker Associated Cancers
α-fetoprotein (AFP) Hepatocellular carcinoma, nonseminomatous testicular
germ-cell tumors
β-human chorionic gonadotropin (hCG) Trophoblastic tumors, choriocarcinoma
Calcitonin Medullary carcinoma of the thyroid
Carcinoembryonic antigen (CEA) Carcinomas of the lung, pancreas, stomach, breast, colon
CA-125 Ovarian epithelial carcinoma
CA19-9 Pancreatic adenocarcinoma
Placental alkaline phosphatase Seminoma
Prostatic acid phosphatase Prostate cancer
Prostate-specific antigen (PSA) Prostate cancer
S-100 Melanoma, neural-derived tumors, astrocytoma
►►Paraneoplastic Syndromes
Syndrome Neoplasm Mechanism
Carcinoid syndrome Carcinoid tumor (metastatic, bronchial, ovarian) Serotonin, bradykinin
Cushing syndrome Small cell carcinoma of the lung, neural tumors ACTH, ACTH-like peptide
Hypercalcemia Squamous cell carcinoma of the lung; breast, renal, PTH-related peptide, TGF-α, TNF, IL-1
and ovarian carcinomas
Lambert-Eaton myasthenic Small cell carcinoma of the lung Antibodies against presynaptic voltage-gated
syndrome Ca2+ channels at the neuromuscular junction
Polycythemia Renal cell carcinoma, hepatocellular carcinoma, Erythropoietin
cerebellar hemangioblastoma
SIADH Small cell carcinoma of the lung; intracranial ADH
neoplasms
Definition of abbreviations: ACTH, adrenocorticotropic hormone; IL, interleukin; TGF, transforming growth factor;
TNF, tumor necrosis factor; PTH, parathyroid hormone; SIADH, syndrome of inappropriate antidiuretic hormone
162
►►Grading and Staging
Grade • An estimate of the cytologic malignancy of a tumor, including the degree of anaplasia and number of mitoses.
• Nuclear size, chromatin content, nucleoli, and nuclear-to-cytoplasmic ratio are all used.
GENERAL PRINCIPLES │ 8. Pathology
Stage • T he clinical estimate of the extent of spread of a malignant tumor. Low stage means a localized tumor. Stage rises as
tumors spread locally then metastasize.
• TNM is typically used; T = size of tumor; N = node involvement; M = metastases
►►Cancer Incidence and Mortality
Incidence Males Females
Breast: 30%
Prostate: 29% Lung and bronchus: 14%
Colon and rectum: 9%
Lung and bronchus: 14% Females
Lung and bronchus: 26%
Colon and rectum: 9% Breast: 15%
Colon and rectum: 9%
Mortality Males
Lung and bronchus: 28%
Prostate: 11%
Colon and rectum: 8%
163
Pharmacology/Therapeutics
Chapter 9
Pharmacokinetics
Key Concepts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166–167
Drug Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
Pharmacodynamics
Key Concepts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
Signal Transduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
Toxicology
Management of the Poisoned Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
Signs, Symptoms, and Treatments for Common Toxic Syndromes . . . . . . . . . . . 170
Signs, Symptoms, and Treatments for Heavy Metal Poisoning . . . . . . . . . . . . . . . 171
Summary of Antidotes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
Autacoids
Histamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
Serotonin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
Angiotensin II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
Antineoplastic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176–177
Natural Medicinals and Nutrional Supplements
Natural Medicinals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
Purified Nutritional Supplements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
Drug Development and Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
165
GENERAL PRINCIPLES │ 9. Pharm/Therapeutics Pharmacokinetics
►►Key Concepts
Volume of Dose • Vd estimates the fluid volume into which the drug
distribution Vd = C0 has distributed (one needs to extrapolate plasma
(apparent) concentration at time zero).
C0= plasma concentration at time zero • T he lower the C0, the higher the Vd, and vice versa
(i.e., inversely related).
Clearance Rate of drug elimination
Plasma drug concentration • Drugs stored in nonfluid compartments like fat may
Cl = have a Vd greater than TBW (e.g., lipid-soluble
drugs, thiopental).
• Drugs that bind strongly to plasma proteins have a
Vd that approaches plasma volume.
• Approximate Vd values (weight 70 kg)
plasma volume (3 L), blood (5 L), extracellular fluid
(12−14 L), TBW (40−42 L)
Clearance is the theoretical volume of blood totally
cleared of drug/unit time. It represents the ratio of drug
elimination to its plasma concentration. For a drug with
first-order elimination, clearance is constant.
Elimination Elimination is synonymous with termination of drug action. The two primary mechanisms are hepatic metabolism
to inactive metabolites or renal excretion.
First-Order Elimination Zero-Order Elimination
Units of Drug First Order A constant fraction of Units of Drug Zero Order A constant amount of
Time drug is eliminated with Time drug is eliminated with
time. time. Half-life is not
applicable.
Most drugs have
first-order elimination. Examples: ethanol
(except at low blood
levels), phenytoin, and
aspirin (high doses)
Half-life t1/2 = 0.7 × Vd Half-life is the time it takes for the amount or concentration of a drug to
Cl fall to 50% of a previous estimate. It is constant for drugs eliminated by first-
order kinetics.
Steady state Plasma drug concentrations remain relatively constant over time. As a rule, it takes 4 to 5 half-lives to achieve
steady state (rise in concentration: 50% at 1 half-life; 75% at 2 half-lives; 87.5% at 3 half-lives; 93.75% at 4 half-
lives. For elimination, decline in concentration is similar: 50% remains at 1 half-life; 25% at 2 half-lives; 12.5% at 3
half-lives; 6.25% at 4 half-lives.)
Bioavailability Plasma Drug Concentration intravascular dose
(F) (e.g., IV bolus)
The fraction of the administered drug that reaches the
systemic circulation.
extravascular dose F = AUCPO (AUC = area under the curve,
(e.g., oral) AUCIV PO = oral, IV = intravenous)
By definition, intravenous drug administration has an F
� of 1 (100%).
Time
Definition of abbreviations: AUC, area under the curve; F, bioavailability; IV, intravenously; PO, by mouth; TBW, total body weight.
(Continued)
166
►►Key Concepts (Cont'd.) GENERAL PRINCIPLES │ 9. Pharm/Therapeutics
First-pass effect With oral administration, drugs are absorbed into the portal circulation and initially distributed to the liver. For some
drugs, their rapid hepatic metabolism decreases bioavailability. This can be avoided by giving the drug by an
alternate route (e.g., sublingual, transdermal).
Maintenance MD = Cl × CP A maintenance dose is given to maintain a relatively constant plasma concentration.
dose F It is equal to the rate of elimination.
Loading dose Vd × CP If therapeutic plasma concentrations are needed quickly and the Vd is large, a
F loading dose may be given to produce the desired drug levels (fill up the Vd) without
LD = the typical delay of 4 to 5 half-lives.
Definition of abbreviation: CP, desired plasma concentration
Drug Metabolism
Biotransformation is the conversion of drugs to more water-soluble drugs that can be more readily excreted. There are two main types of
metabolic reactions: phase I and phase II.
Phase I The parent drug becomes more water-soluble by oxidation, reduction, or hydrolysis by cytochrome P450
isozymes (also called mixed function oxidases) located in smooth endoplasmic reticulum in liver, and
CYP450 in the GI, lungs, and kidney to a lesser extent. Often the drug is converted to compounds with little or no
1A2 pharmacologic activity; in other instances, the metabolites retain pharmacologic activity.
2C9
2D6 Substrate Example Inducers Inhibitors Genetic
Polymorphisms
Theophylline Aromatic hydrocarbons Quinolones No
Acetaminophen (smoke) Macrolides
Yes
Phenytoin Cruciferous vegetables —
Warfarin General inducers* Yes
Many cardiovascular and Haloperidol
CNS drugs None known Quinidine
3A4 60% of drugs in PDR General inducers* General inhibitors† No
Phase II Grapefruit juice
Conjugation reactions may follow phase I or can occur on the parent drug. Examples include
glucuronidation, acetylation, sulfation, glutathione conjugation, and methylation. Phase II reactions
lead to inactive molecules, which are polar and usually renally excreted. All phase II reactions use enzymes
called transferases.
Definition of abbreviations: PDR; Physician's Desk Reference.
* G eneral inducers: anticonvulsants (barbiturates, phenytoin, carbamazepine), antibiotics (rifampin), chronic alcohol, glucocorticoids.
† G eneral inhibitors: antiulcer medications (cimetidine, omeprazole), antibiotics (erythromycin, clarithomycin, macrolides) protease inhibitors,
azole antifungals, acute alcohol.
167
GENERAL PRINCIPLES │ 9. Pharm/Therapeutics Pharmacodynamics
►►Key Concepts
Agonist An agonist is a drug that binds to a receptor and activates it.
Partial agonist A partial agonist is a drug that binds to a receptor but does not elicit a 100% response. It will elicit a partial
response when administered alone. When administered with a full agonist, it acts as an antagonist because
it displaces the full agonist from the receptor.
Graded dose− B A graded dose−response curve depicts increasing responses to
response curve increasing drug doses.
Competitive Efficacy AC Potency: the measure of how much drug is required to produce
antagonist % Response a given effect. It is typically expressed as the concentration that
Log Dose of Drug can elicit a 50% response (EC50).
Noncompetitive Potency
antagonist Efficacy: the maximal effect a drug can produce. It is also known
as maximal efficacy.
Kd
Physiologic A partial agonist has a lower efficacy than a full agonist. It can be
antagonist less potent (C) or more potent (A) than a full agonist (B). (See
figure to left.)
control competitive A competitive antagonist binds to the receptor without activating
100 the effector system. It can be overcome by increasing the agonist
% Response dose. This is seen as a parallel right shift in the dose−response
curve.
noncompetitive
Log Dose of Drug A noncompetitive antagonist binds to the receptor without
activating the effector system. It cannot be overcome by
increasing the agonist dose. This is seen as a downward shift in
the dose−response curve.
FigurTehI-e2-4c.oDn-cReCnturravteiosnofoAfndtarguogntishtastabnidnPdostetonti5a0to%rs of the receptors
Substances that produce opposing physiologic effects, but do not exert their mechanism of action at the same
receptor
Quantal dose− A quantal dose−response curve depicts the dose of drug needed to produce a predetermined response in a
response curve population. It is the percent of population responding versus log (dose).
Therapeutic index Therapeutic Death The therapeutic index is the ratio of the drug dose required
(TI) 100 effect to produce a toxic or lethal effect to the dose needed for a
therapeutic effect.
% of population 50 TI = TD50 or LD50
responding ED50 ED50
0 ED50, TD50, and LD50 are the median effective, toxic, and lethal
ED50 doses in d5r0u%�g;o↓f the studied population, respectively.
Log [drug] TI, safe TI, unsafe drug
LD50 ↑
168
►►Signal Transduction GENERAL PRINCIPLES │ 9. Pharm/Therapeutics
G-protein−coupled receptors* These receptors consist of one polypeptide with seven-transmembrane−spanning regions. When
bound by an agonist, the trimeric (α, β, γ) GTP-binding protein (G protein) is activated. The α
component usually interacts with the effector molecules.
The most common G proteins and their receptors are as follows:
G protein Receptors Effector Second messenger response
Gs β1, β2,D1, H2, V2 Adenylyl cyclase ↑ cAMP
Gi α2, M2, D2 Adenylyl cyclase ↓ cAMP
Gq α1, M1, M3, H1, V1 Phospholipase C ↑ IP3 (↑ Cai2+), DAG
Ligand-gated channels Activation of receptors within ion channels may directly open the channel, e.g., nicotinic ACh (Na+/
Intracellular receptors K+), GABAA (Cl−), NMDA (Ca2+/Na+) receptors, or may regulate the ion channel’s response to an
agonist, e.g., benzodiazepine or barbiturate sites on the GABAA receptor.
Lipid-soluble agents diffuse across the plasma membrane to bind intracellular receptors (e.g.,
steroid receptors, thyroid receptors). This permits receptor binding to nuclear DNA sequences that
modify gene expression.
Ligand-regulated These receptors have extracellular ligand binding sites and intracellular catalytic sites. Ligand
transmembrane enzymes* binding causes dimerization and activates the enzyme activity (often a tyrosine kinase). Examples:
insulin and growth factor receptors.
Transmembrane receptors These also form dimers when activated, then activate a separate cytoplasmic tyrosine kinase (Janus
that activate a separate kinases; JAKs). The kinase phosphorylates STAT factors (signal transducers and activators of
tyrosine kinase transcription). STAT dimers then regulate transcription. Examples: cytokine and growth hormone
receptors.
* Figures of these pathways can be found on pages 84–85, Cell Signaling.
169
GENERAL PRINCIPLES │ 9. Pharm/Therapeutics Toxicology
►►Management of the Poisoned Patient
There are many facets of managing the poisoned patient, including supportive care, poison identification, decontamination, enhancing
elimination, and administration of antidotes.
Decontamination Syrup of ipecac (induces vomiting), gastric lavage (“stomach pumping”), activated charcoal
(absorbs drug)
Enhancing • M any drugs are weak acids or bases and can be in nonionized or ionized forms. Nonionized drugs
elimination are lipid soluble (cross membranes); ionized drugs are water soluble (renally excreted)
• The urine pH can be manipulated to increase drug elimination
Weak acid: R -COOH ↔ R-COO– + H+ (e.g., aspirin)
(Increase excretion by giving bicarbonate to trap drug in basic environment)
Weak base: R -NH+3 ↔ R-NH2 + H+ (e.g., amphetamines)
(Increase excretion with NH4Cl to trap drug in acidic environment)
►►Signs, Symptoms, and Treatments for Common Toxic Syndromes
Compounds Signs and Symptoms of Toxicity Treatment
AChE inhibitors Miosis, salivation, sweating, GI cramps, diarrhea, seizures, Respiratory support; atropine plus pralidoxime
anxiety/agitation, muscle fasciculations followed by muscle (2-PAM, AChE-reactivating agent for
paralysis (including diaphragm), respiratory failure, coma organophosphate inhibitors)
Atropine and ↑ HR, ↑ BP, hyperthermia (hot, dry skin), ↓ GI motility, Control CV symptoms and hyperthermia plus
muscarinic urinary retention, mydriasis, delirium, hallucinations, physostigmine (crosses BBB)
blockers seizures, coma
Carbon monoxide Hyperbaric O2 and decontamination
(>10% carboxyHb) Headache, dizziness, nausea/vomiting, shortness of
breath, chest pain, ↑ HR, ↓ BP, arrhythmias, confusion, Control CV symptoms, hyperthermia, and
CNS stimulants coma seizures; BZs or antipsychotics may be
beneficial
Opioid analgesics Anxiety/agitation, hyperthermia (warm, sweaty skin), Ventilatory support; naloxone at frequent
mydriasis, ↑ HR, ↑ BP, psychosis, seizures intervals
Salicylates
Lethargy, sedation, coma, ↓ HR, ↓ BP, miosis,
Sedative-hypnotics hypoventilation, respiratory failure, ↓ GI motility
and ethanol
SSRIs Confusion, lethargy, hyperventilation, ototoxicity, Correct acidosis and electrolytes, urinary
hyperthermia, dehydration, hypokalemia, acid-base alkalinization, possible hemodialysis
disturbances, seizures, coma
Ventilatory support—flumazenil if BZs
Disinhibition, lethargy, stupor, coma, ataxia, nystagmus, implicated
hypothermia, respiratory failure
Control hyperthermia and seizures—possible
Agitation, confusion, coma, muscle rigidity, hyperthermia, use of cyproheptadine and BZs
seizures, autonomic instability
Tricyclic Mydriasis, hyperthermia (hot, dry skin), 3 Cs Control seizures and hyperthermia, correct
antidepressants (convulsions, coma, and cardiotoxicity) acidosis plus possible antiarrhythmics
Definition of abbreviations: AChE, acetylcholinesterase; BBB, blood−brain barrier; BP, blood pressure; BZs, benzodiazepines; CNS, central
nervous system; CV, cardiovascular; GI, gastrointestinal; HR, heart rate; SSRIs, selective serotonin reuptake inhibitors.
170
►►Signs, Symptoms, and Treatments for Heavy Metal Poisoning GENERAL PRINCIPLES │ 9. Pharm/Therapeutics
Metals Source Signs and Symptoms Treatment*
Arsenic Wood preservatives, Acute: GI distress, garlic breath, “rice water” stools, Dimercaprol, penicillamine,
insecticides, occupational, hypotension succimer
environmental
Chronic: paresthesias, stocking-glove neuropathy, pallor Supportive care
from anemia, skin
Arsine gas: headache, N/V, abdominal pain, dyspnea,
jaundice
Iron Iron supplements, multivitamin Occurs mainly in children; severe GI distress, GI Deferoxamine
supplements bleeding, hepatocellular injury, seizures, shock, coma
Lead Tap water, leaded paint chips, Acute: abdominal (colic, N/V), CNS (headaches, ataxia, EDTA, dimercaprol, succimer
glazed kitchenware, etc. seizures, coma, encephalopathy)
Chronic: anemia (inhibits heme synthesis), neuropathy
(wristdrop), GI symptoms, nephropathy, developmental
delays, growth retardation, decreased fertility, stillbirths
Mercury Dental amalgams, Acute: vapor inhalation (elemental)—chest pain, Dimercaprol, penicillamine,
electroplating, batteries, wood dyspnea, pneumonitis, confusion succimer
preservatives, occupational,
contaminated foods, old Acute: tremors, gingivitis, CNS disturbances, GI distress,
thermometers renal failure
Chronic: renal failure, dementia, acrodynia
Organic: CNS (paresthesias, auditory and visual loss,
movement disorders)
Definition of abbreviations: CNS, central nervous system; GI, gastrointestinal; EDTA, ethylenediaminetetraacetic acid; N/V, nausea
and vomiting.
*Need to remove patient from source; decontamination is also important part of management.
171
GENERAL PRINCIPLES │ 9. Pharm/Therapeutics ►►Summary of Antidotes
Antidote Type of Poisoning
Acetylcysteine Acetaminophen
Atropine AChE inhibitors
Deferoxamine Iron
Digoxin antibodies Digoxin
Dimercaprol (BAL) Arsenic, mercury (inorganic, elemental), lead (with EDTA if severe poisoning); succimer and unithiol
now used more frequently
EDTA Primarily for lead poisoning
Esmolol Theophylline, caffeine, β agonists
Ethanol Methanol, ethylene glycol
Flumazenil Benzodiazepines, zolpidem, suggested for zaleplon
Fomepizole Methanol, ethylene glycol
Glucagon β blockers
Naloxone Opioid analgesics
Oxygen Carbon monoxide
Penicillamine Copper, Wilson disease, adjunctive in iron and arsenic intoxication
Physostigmine Anticholinergics: atropine, antihistamine, antiparkinsonian—not tricyclic antidepressants
Pralidoxime (2-PAM) Organophosphate cholinesterase inhibitors
Protamine Heparins
Succimer Lead, arsenic, mercury
Vitamin K Warfarin and coumarin anticoagulants
Activated charcoal Nonspecific: all oral poisonings except Fe, CN, Li, solvents, mineral acids, or corrosives
Definition of abbreviations: AChE, acetylcholinesterase; EDTA, edetate calcium disodium, ethylenediaminetetraacetic acid.
172
Autacoids GENERAL PRINCIPLES │ 9. Pharm/Therapeutics
Autacoids are endogenously produced substances that do not fit well in other classifications such as hormones or neurotransmitters. The
autacoids include histamine, serotonin, vasoactive peptides, and prostaglandins (see page 54).
►►Histamine
Synthesis H istidine Histidine decarboxylase Histamine
Location Circulating basophils and tissue mast cells, GI tract, skin, lung
Degranulation • Liberation of histamine from mast cells via IgE-mediated hypersensitivity reactions, trauma, drugs, and venoms
• ↓ cAMP favors release; ↑ cAMP (via β-adrenergic and glucocorticoid stimulation) ↓ release
• Other substances released include kallikrein, kinins, prostaglandins, SRS-A
Histamine Receptors
Receptor Second Messenger Distribution Action
H1 Gq; ↑ IP3, DAG Smooth muscle Vasodilation (via NO), ↑ bronchoconstriction, activates nociceptive
receptors
H2 Gs; ↑ cAMP Stomach, ↑ gastric acid secretion
smooth muscle
Pharmacologic Agents
Agent Mechanism of Action Clinical Uses Notes/Toxicity
H1 antagonists: Competitively inhibit H1 • Allergic reactions • Muscarinic block (sedation, dry
Diphenhydramine receptors mouth)
Promethazine • Motion sickness
Chlorpheniramine
Hydroxyzine • OTC: sleep aids and cold
Fexofenadine* medications
Loratadine*
Cetirizine*
H2 antagonists: Competitively inhibit H2 • Peptic ulcer disease† Cimetidine: P450 inhibition,
Cimetidine receptors → reduce gastric • GERD antiandrogen effect
acid secretion† • Zollinger Ellison syndrome
Ranitidine
Famotidine
Nizatidine
Definition of abbreviations: GERD, gastroesophageal reflux disease; GI, gastrointestinal; IgE, immunoglobulin E; SRS-A, slow-reacting
substance of anaphylaxis.
*No CNS entry (less sedating) and no muscarinic block; loratadine (Claritin), fexofenadine (Allegra), cetirizine (Zyrtec)
†Not as efficacious as proton pump inhibitors
173
GENERAL PRINCIPLES │ 9. Pharm/Therapeutics ►►Serotonin
Synthesis and Tryptophan hydroxylase 5HT MAOA 5HIAA
degradation
Tryptophan
Location Enterochromaffin cells in the gut, CNS neurons, platelets (primarily just storage)
Serotonin Receptors
Receptor Second Messenger Action
5HT1(A, B, D, E, F) Gi; ↓ cAMP • CNS
• Behavioral effects (sleep, feeding, thermoregulation, anxiety)
• Vasoconstriction
5HT2(A, B, C) Gq; ↑ IP3, DAG • CNS
• Behavioral effects
• Smooth muscle contraction
• Platelet aggregation
5HT3 Ion channel • CNS (area postrema), PNS
• Emesis
• Anxiety
5HT4 Gs; ↑ cAMP • CNS: neuronal excitation
• GI motility
Pharmacologic Agents
Agent Mechanism of Action Clinical Uses Notes/Toxicity
Sumatriptan 5HT1D agonist Migraine headaches
Naratriptan
Other “-triptans”
Buspirone 5HT1A partial agonist Anxiety disorders Lower addiction potential than other drugs
like benzodiazepines
Ondansetron 5HT3 antagonist Emesis Mainly for postoperative or chemotherapy-
Granisetron induced nausea and vomiting
Other “-setrons”
SSRIs: Selectively block 5HT • Anxiety disorders • Sexual dysfunction
Citalopram reuptake • Depression
Fluoxetine • D rug interactions: serotonin syndrome
Fluvoxamine with MAO inhibitors, TCAs, meperidine,
Paroxetine and St. John’s wort
Sertraline
Ergot alkaloids: Agonists, partial agonists, • P ostpartum hemorrhage Ergotism (“St. Anthony’s Fire”):
Ergonovine and antagonists at (ergonovine, ergotamine)
Ergotamine 5HT and α-adrenergic − Mental disorientation
Methysergide receptors; some are • M igraine headaches − Hallucination
Bromocriptine* agonists at DA receptors* (ergotamine [for acute − Convulsions
LSD attacks], methysergide − Muscle cramps
[prophylaxis]) − Dry gangrene of extremities
• P arkinson disease,
hyperprolactinemia
(bromocriptine, pergolide)
• Abuse (LSD)
MAO inhibitors: Inhibit metabolism of 5HT, Depression • Non-selective MAO inhibitors
Phenelzine NE, and DA by MAO • Tyramine (red wine, cheese) ingestion →
Tranylcypromine
hypertensive crisis
Definition of abbreviations: DA, dopamine; 5-HT, 5-hydroxytrypamine; 5-HIAA, 5-hydroxyindoleacetic acid; LSD, d-lysergic acid
diethylamide; MAO, monoamine oxidase; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressants.
174
►►Angiotensin II Synthesis and Actions GENERAL PRINCIPLES │ 9. Pharm/Therapeutics
Angiotensinogen Renin (kidney) Angiotensin I Bradykinin
(from liver)
Angiotensin-
Converting
Enzyme
(lungs)
Angiotensin II inactivation
Adrenal cortex AT-1 blood vessels
receptors
Aldosterone Vasoconstriction
secretion
Pharmacologic Agents
Agent Mechanism of Action Clinical Uses Notes/Toxicity
ACE Inhibitors Inhibits conversion of AT-I to • Hypertension • Dry cough
AT-II by ACE • CHF • Angioedema
Captopril • Myocardial infarction • Hypotension
Enalapril* Also inhibits the inactivation • Diabetic nephropathy • Acute renal failure
Benazepril* of bradykinins by kininase II, • ↓ Aldosterone
potentiating their vasodilatory • Hyperkalemia
effect • Fetal renal toxicity;
contraindicated in pregnancy
AT1-receptor Competitively inhibit receptor • Hypertension • Common alternative to ACE-inhibitors
antagonists: for AT-II • CHF if patient cannot tolerate adverse
• Diabetic nephropathy reactions (e.g., cough)
Losartan
Valsartan • Does not block BK degradation
• Similar BP effects and toxicity profile as
ACE inhibitors (but no cough)
Renin inhibitor: Blocks formation of AT-I Hypertension • Similar BP effects as ACE inhibitors
Aliskiren (and therefore AT-II) via renin • Does not block BK degradation
inhibition • Headache, diarrhea
Definition of abbreviations: ACE, angiotensin-converting enzyme; AT-I, angiotensin I; AT-II, angiotensin II; BK, bradykinin;
CHF, congestive heart failure.
*Ester prodrugs of ACE inhibitor converted to active form by liver
175
GENERAL PRINCIPLES │ 9. Pharm/Therapeutics Antineoplastic Agents
These agents are used to treat various neoplasms. Although the mechanism of action varies, each agent hinders cell replication
in some way. Specificity relies on differential effect between neoplastic cells and normal tissue. The mechanism of action may
be cell-cycle specific (affecting cells in all stages except G0) or cell-cycle nonspecific.
Class Mechanism Indications Toxicities
Antimetabolites Cell-cycle specific (CCS). Inhibit synthesis of nucleic acids and thus protein synthesis.
Methotrexate • A folic acid analog that Neoplastic indications: leukemia, Suppresses bone marrow
inhibits dihydrofolate lymphomas, breast cancer, reversibly; folinic acid
reductase; decreased choriocarcinoma (leucovorin) is used to “rescue”;
dTMP levels hinder fatty change in liver
DNA synthesis and thus Nonneoplastic indications:
protein synthesis rheumatoid arthritis, psoriasis,
termination of pregnancy
• S-phase specific (e.g., ectopic)
5-Fluorouracil (5-FU) • P yrimidine Breast, ovarian, colon, head Irreversible myelosuppression
antimetabolite is and neck cancers, basal cell and photosensitivity, GI irritation,
converted to 5-F-dUMP, carcinomas and keratoses (use alopecia
which when bound topically)
to folic acid, inhibits
thymidylate synthase.
This prevents dTMP
synthesis, thus inhibiting
DNA and protein
synthesis.
• S-phase specific
Cytarabine (Ara-C) • Pyrimidine Acute leukemias BMS, GI irritation, ↑ doses →
antimetabolite neurotoxicity
• Inhibits DNA
polymerases
• S-phase specific
6-Mercaptopurine • A ctivated by Aacute leukemias, CML, non- • BMS,
(6-MP) hypoxanthine- Hodgkin lymphoma hepatotoxicitycoadministration
guanine phosphori- with allopurinol increases toxicity
bosyltransferase (6-MP metabolized by xanthine
(HGPRT) oxidase)
• I nhibits purine • Azathioprine forms 6-MP
synthesis, inhibiting
nucleic acid synthesis
• S-phase specific
Alkylating Agents Cell cycle-nonspecific (CCNS). This class of agents causes alkylation of DNA, leading to
cross-linking, abnormal base pairing, or DNA strand breakage.
Busulfan Alkylates DNA CML Pulmonary fibrosis,
hyperpigmentation, and adrenal
insufficiency
Cyclophosphamide Alkylates DNAattacks Non-Hodgkin lymphoma; BMS and hemorrhagic cystitis
guanine N7, induces ovarian and breast cancers; (can be ↓ by mesna, which traps
cross-linking neuroblastoma acrolein, a toxic metabolite)
Nitrosoureas (lomustine, • Alkylates DNA Brain tumors Neurologic
carmustine)
• Crosses blood–brain
barrier
Definition of abbreviations: BMS, bone marrow suppression; CML, chronic myelogenous leukemia. (Continued)
176
►►Antineoplastic Agents (Cont’d.) GENERAL PRINCIPLES │ 9. Pharm/Therapeutics
Class Mechanism Indications Toxicities
Cisplatin, carboplatin Alkylates DNA Testicular, bladder, lung, and Nephrotoxic, neurotoxicity
ovarian carcinomas (deafness, tinnitus)
Procarbazine Alkylates DNA Hodgkin disease (MOPP*) BMS, pulmonary toxicity, neurotoxic,
leukemogenic
Antibiotics Structurally dissimilar subclass of drugs. Mechanisms of action vary.
Doxorubicin Intercalates DNA, Hodgkin lymphoma (ABVD†), Cardiotoxicdexrazoxane
creating breaks. Hinders breast, endometrial, lung, (treatment to inhibit free radical
DNA replication and ovarian CAs, myeloma, formation; may protect against
transcription. sarcomas cardiotoxicity), BMS, alopecia, GI
distress
Bleomycin • Generates free radicals Lymphomas, testicular, skin CA Pulmonary fibrosis,
→ DNA strand scission mucocutaneous reactions (blisters,
alopecia), hypersensitivity
• G2 phase reactions
Hormones/ May inhibit hormone-dependent tumor growth.
Hormone Antagonists
Prednisone Induces apoptosis of Chronic lymphocytic leukemia Typical symptoms of glucocorticoid
lymphoid cells (CLL), Hodgkin lymphoma excess, including Cushing
(MOPP*), autoimmune disease syndrome
Tamoxifen Selective estrogen Breast cancer Hot flashes, increased risk of
receptor modulator endometrial carcinoma
(SERM). Prevents
estrogen from binding
estrogen receptor–
positive breast CA cells,
leading to involution of
estrogen-dependent
tumors.
Plant Alkaloids Cell-cycle specific drugs. Most prevent the assembly of microtubules and the formation of the
mitotic spindle.
Vinblastine • Inhibits microtubule/ Lymphoma, Wilms tumor, BMS
spindle formation choriocarcinoma
• M-phase specific
Vincristine • Inhibits microtubule/ Same as vinblastine, MOPP* Neurotoxic, GI distress
spindle formation (is Oncovin)
• M-phase specific
Paclitaxel • S tabilizes microtubules Ovarian and breast carcinomas BMS
so that spindle cannot
break down
• M-phase specific
Etoposide • Inhibits topoisomerase Small cell carcinoma, prostate BMS, GI irritation, alopecia
II, ↑ DNA degradation cancer, testicular carcinoma
• Late S/early G2 phase
†ABVD: Adriamycin® (doxoribicin), bleomycin, vinblastine, decarbazine
*MOPP: mechlorethamine, vincristine (Oncovin®), procarbazine, prednisone
177
GENERAL PRINCIPLES │ 9. Pharm/Therapeutics Natural Medicinals and Nutritional Supplements
Please note that these substances are not FDA-approved for any conditions and there are variable amounts of evidence regarding effi-
cacy. However, many of your patients may be taking herbal medicines such as these, and familiarity with these agents is useful.
►►Natural Medicinals
Name Medicinal Use(s) Possible Mechanism(s) Side Effects/Interactions
↑ ILs and TNF
Echinacea ↓ Cold symptoms GI distress, dizziness,
headache
Ephedra (Ma Huang) Bronchodilator, cold symptoms, Indirect acting
Insomnia, palpitations,
mild CNS stimulant sympathomimetic tachycardia; higher doses:
hypertension, cardiac
Garlic ↓ Cholesterol, atherosclerosis Inhibits HMG-CoA reductase arrhythmias, toxic psychosis
and ACE
Allergies, hypotension,
Gingko Intermittent claudication; Antioxidant, free radical antiplatelet actions; caution
cognitive improvement scavenger, ↑ NO advised when used with
anticoagulants
Ginseng Possible ↑ in mental and Unknown
Milk thistle physical performance Anxiety, GI distress, insomnia,
antiplatelet actions; caution
Saw palmetto Limits hepatic injury from Inhibits P450 advised when used with
St. John’s wort Amanita mushroom poisoning, anticoagulants
viral hepatitis, alcohol, 5α-reductase inhibitor and
acetaminophen androgen receptor antagonist Insomnia, nervousness,
May enhance brain 5HT hypertension, mastalgia,
BPH treatment functions vaginal bleeding
Depression None reported
GI pain, ↓ libido, headache,
hypertension
Major drug interactions:
serotonin syndrome with
SSRIs, MAOIs; induces P450,
leading to ↓ effects of multiple
drugs
►►Purified Nutritional Supplements
Name Medicinal Use(s) Side Effects
Coenzyme Q10 Hypertension, coronary artery disease, chronic Well-tolerated, some GI disturbance
(ubiquinone) stable angina, CHF
Females: androgenization and concern regarding
Dehydroepiandrosterone Androgen precursor advocated for treatment of CV disease and breast cancer
(DHEA) AIDS ( ↑ CD4 in females), Alzheimer disease
and “aging,” diabetes, hypercholesterolemia, and Males: feminization in young and concern in
SLE ( ↓ in symptoms and “flare-ups” in females) elderly regarding BPH and cancer
Glucosamine Osteoarthritis Well tolerated, some GI disturbances
Melatonin
Serotonin derivative used for “jet-lag” and sleep Drowsiness, sedation, headache.
disorders Contraindicated in pregnancy, in women trying
to conceive (↓ LH), and in nursing mothers
(↓ prolactin)
178
Drug Development and Testing GENERAL PRINCIPLES │ 9. Pharm/Therapeutics
Preclinical IND Phase 1 Phase 2 Phase 3 NDA Phase 4
25-50 normal 100-200
In vitro testing; Proposal to the volunteers✝ patients 1000-5000 Request to Post-marketing
animal testing FDA for human patients; market new surveillance (if
(at least 2 testing; includes Safety and Efficacy double-blind agent FDA approved
different preclinical data pharmacokinetics studies used NDA)
species) and proposals
for the clinical Efficacy, side Physicians
Biologic activity trials effects report toxicities
and safety that may be
now apparent
with a larger
sample size.
*Definition of abbreviations: IND: Investigational New Drug application; NDA: New Drug Application
✝ If the agent is known to be toxic (e.g., antineoplastic, AIDS drug), volunteer patients will be used instead
179
Section II
Organ Systems
The Nervous System
Chapter 1
Development of the Nervous System Accommodation-Convergence Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
Clinical Correlations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
Central Nervous System Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184 Eye Movement Control Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
Congenital Malformations of the Nervous System . . . . . . . . . . . . . . . . . . . . . . . . 185 Trigeminal Nerve (V)/Facial Nerve (VII) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
Vestibular System (VIII) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
Peripheral Nervous System Auditory System (VIII) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
Autonomic and Somatic Nervous Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186 Brain Stem Lesions
Parasympathetic and Sympathetic Nervous Systems . . . . . . . . . . . . . . . . . . . . . . 186
Parasympathetic = Craniosacral Outflow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 Medulla . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212
Sympathetic = Thoracolumbar Outflow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 Pons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212
Autonomic Effects on Organ Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187–188 Midbrain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
Cholinergic Transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
Cholinergic Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189–191 Cerebellum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
Predominant Tone and the Effect of Ganglionic Blockers . . . . . . . . . . . . . . . . . . 191
Adrenergic Transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192 Diencephalon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
Adrenergic Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193–194
Basal Ganglia
Meninges, Ventricular System, and Venous Drainage
Basal Ganglia Components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
Meninges and Meningeal Spaces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 Diseases of the Basal Ganglia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
Meningitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 Treatment for Parkinson Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
Organisms Causing Bacterial Meningitis by Age Group . . . . . . . . . . . . . . . . . . . . 195
CSF Parameters in Meningitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196 Limbic System
Viral Encephalitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
Ventricular System and Venous Drainage . . . . . . . . . . . . . . . . . . . . . . . . . . . 196–197 Limbic Structures and Functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
Hydrocephalus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197 Clinical Correlations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
Neurohistology and Pathologic Correlates Cerebral Cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
Cell Types of the Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198 Key Features of Lobes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
Disorders of Myelination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198–199 Alzheimer Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
Tumors of the CNS and PNS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
Primary Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199 Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
Spinal Cord Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
Creutzfeldt-Jakob Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
General Spinal Cord Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200 Pick Disease (Lobar Atrophy) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
Descending Pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201 CNS Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
Upper Versus Lower Motor Neuron Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201 Cerebral Herniations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
Commonly Tested Muscle Stretch Reflexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
Ascending Pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202 Blood Supply . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222–223
Dorsal Column-Medial Lemniscus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
Anterolateral (Spinothalamic) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203 Cerebrovascular Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
Classic Spinal Cord Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
Seizures and Anticonvulsants
Cranial Nerves and Brain Stem
Seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
Cranial Nerves: Functional Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204–205 Anticonvulsants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
Skull Base Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205 Newer Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
Visual System Opioid Analgesics and Related Drugs
Visual Field Defects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206 Individual Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
Anatomy of the Eye and Glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206 Characteristics of Opioid Analgesics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
Pharmacology of the Eye . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
Drugs Used to Treat Glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207 Local Anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
Pupillary Light Reflex Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
General Anesthetics
Inhalational Anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228
Intravenous Anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228
183
ORGAN SYSTEMS │ 1. The Nervous System Development of the Nervous System
Neurulation Neural plate Neuroectoderm Neural
groove
Notochordal Neural
• N eurulation begins in the third week of process fold
fetal development.
Ectoderm A
• T he notochord induces the overlying Mesoderm
ectoderm to form the neural plate. A Endoderm Notochord (induces formation
of the nervous system)
• B y end of the third week, neural folds Neural
grow over midline and fuse to form neural groove Neural crest
tube.
B
• During closure, neural crest cells form
from neuroectoderm.
Day 18
• Neural tube → brain and spinal cord Neural fold Neural Neural crest
(plus lower motoneurons, preganglionic tube Alar plate (sensory)
neurons) Rostral
neuropore (closes at C Basal plate (motor)
• Brain stem and spinal cord have an day 25) Neural crest
alar plate (sensory) and a basal plate B
(motor); plates are separated by the C Failure to close results
sulcus limitans. in anencephaly, causing
D polyhydraminos and
• Neural tube → 3 primary vesicles → increased alpha-feto
5 primary vesicles protein
• N eural crest → sensory and Caudal D
postganglionic neurons neuropore
(closes at 27D)
• Peripheral NS (PNS): cranial nerves (12 Day 22
pairs) and spinal nerves (31 pairs) Failure to close results
in spina bifida and
increased alpha-
feto protein
►►Central Nervous System Development
Adult Derivatives
5 secondary vesicles Structures Ventricles
3 primary vesicles Telencephalon Telencephalon Cerebral Lateral ventricle
Forebrain Diencephalon hemispheres, most
Midbrain Mesencephalon of basal ganglia
Hindbrain Metencephalon
Neural Myelencephalon Brain stem Diencephalon Thalamus, Third ventricle
tube Spinal cord Spinal cord Mesencephalon hypothalamus, Cerebral aqueduct
subthalamus,
epithalamus
(pineal gland),
retina
Midbrain
Metencephalon Pons, cerebellum Fourth ventricle
Myelencephalon Medulla
184
►►Congenital Malformations of the Nervous System Vertebral arch
Muscle
Condition Types Description Skin ORGAN SYSTEMS │ 1. The Nervous System
Dura and arachnoid
Anencephaly — Failure of anterior neuropore to close Subarachnoid spac
Spinal cord
Brain does not develop Vertebral body
Incompatible with life
Increased AFP D
Spina bifida Failure of posterior neuropore to close
Spina bifida occulta VMeritledberasl tarfcohrm
(Figure A)
MVuesrctleebrae fail to form aSrkoinund spinal cord
Spina bifida with
meningocele No increase in AFP
(Figure B)
Asymptomatic Dura and arachnoid
Vertebral arch
Meninges protrude throughSvubearrtaecbhnraoild dspeafceect
MmSupesicnnleiangboifmidyaewloicthele Spinal cord
(Figure C) Increase in AFP
Vertebral body
Spina bifida with
myeloschisis Skin Meninges and spinal cord protrude through
(Figure D) vertebral defect
Increase in AFP
Dura and arachnoid
SMuboarsatchsneovidesrpeace
SSpinpailncaorldcord can be seen externally
VIenrtcebreraal bsoedyin AFP
Vertebral arch Skin A BC
Muscle
Dura and arachnoid
Subarachnoid space
Spinal cord
Vertebral body
Arnold-Chiari malformation Type I Most common
Mostly asymptomatic
Type II Downward displacement of cerebellar tonsils
Dandy-Walker malformation through foramen magnum
Hydrocephalus
Holoprosencephaly More often symptomatic
Definition of abbreviation: AFP, a-fetoprotein. Downward displacement of cerebellar vermis and
medulla through foramen magnum
Compression of IV ventricle → obstructive
hydrocephaly
Frequent lumbar meningomyelocele
Frequent association with syringomyelia
Failure of foramina of Luschka and Magendie to
open → dilation of IV ventricle
Agenesis of cerebellar vermis and splenium of the
corpus callosum
Most often caused by stenosis of cerebral aqueduct
CSF accumulates in ventricles and subarachnoid
space
Increased head circumference
Incomplete separation of cerebral hemispheres
One ventricle in telencephalon
Seen in trisomy 13 (Patau)
185
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