Drug Toxicology

Chapter 1 introduction to toxicology

• Definition of toxicology
Toxicology is the study of the adverse effects of
chemicals on living organisms.
Two basic functions of toxicology:
(1) Examine the nature of the adverse effects
(2) Assess the probability of these hazards/toxicities
occurring

• Scope of toxicology
 Descriptive Toxicology
 Concerned directly with toxicity testing.
 Provide information for safety evaluation and
regulatory requirements.
 Mechanistic Toxicology
 Concerned with identifying and understanding the
mechanisms of toxic effect.
 Contribute to the design and production of safer
chemicals.
 Regulatory Toxicology
 Decide whether a drug or another chemical poses
a sufficiently low risk to be marked for a stated
purpose.
 Establish standards for the amount of chemicals
permitted, and make principles and approaches
for risk assessment.

• Three R’s of humane animal use

In 1959, Russell and Burch first proposed the three R’s of
humane animal use in research: Replacement, Reduction,
Refinement.

1. Replacement: methods which avoid or replace the use of animals

in research
2. Reduction: use of methods that enable researchers to obtain
comparable levels of information from fewer animals, or to obtain
more information from the same number of animals.
3. Refinement: use of methods that alleviate or minimize potential
pain, suffering or distress, and enhance animal welfare for the
animals used.
The 3Rs have a broader scope than simply encouraging alternatives to
animal testing, but aim to improve animal welfare and scientific quality
where the use of animals cannot be avoided.

Chapter2 essential concepts of toxicology

• What is toxicants? Toxin?
Toxicant:
Substances that are produced by or are byproduct of
anthropogenic (human-made) activities.

Toxin：
Generally refers to toxic substances of animals, plant and
bacterial origin that are produced naturally.

• What is toxicity?
Toxicity:
The ability to cause a deleterious effect to a biological
system.

• General types of toxicity

(1) Local vs systemic toxicity
 Local toxic effect
Refer to those that occur at the site of first contact between the
biological system and the toxicant.
 Systemic toxic effect
They are characterized by the absorption of the chemical and
distribution form the port of entry to a distant site where toxic
effects are produced. Most chemicals act systemically.

(2) Reversible vs irreversible toxic effects

 Reversible effect
are used for adverse effects that diminish once exposure to a
toxicant is stopped.
 Irreversible effect
refer to some toxic effects remain exist after once exposure to a
toxicant, such as some substantial damage, neuronal damage,
tumor.
 The extent of exposure (time and amount) is key factor
to determine whether the toxic effect is reversible or
not.
(3) Immediate Vs Delayed Toxicity
 Immediate effect:
Toxicity occur or develop rapidly after a single administration of
a substance.
 Delayed effect:
Toxicity appear long after the initiation and/or cessation of
exposure to the toxicant.
Carcinogenic effects of chemicals usually have a long latency
period, often 20 to 30 years in humans and several months in
rodents. This reminds us that when study on the delayed
reaction of compounds, we need long term test.
(4) Allergic Vs Idiosyncratic reactions
 Allergic reaction:)
It is a pathological immune response to exogenous chemicals.
 Characteristic：
1) past contact history;
2) does not show a typical "S"- type dose-response curve.
 Idiosyncratic reaction:
A genetic abnormal reaction to exogenous chemicals.

• What is the differences between A type (cumulative type)

and B type (abnormal type) damage response?
• Comparison of A type (cumulative type) and B type
(abnormal type) damage response

• Terms: LD50/MTD/ADI/NOAEL…
• LD50 = a statistically obtained virtual value. It has little
relevance to the individual difference, good
reproducibility and is sensitive in dose-response
 relationship. LD50 is frequently used and represents the
best estimation of the doses required to kill animals.
• Maximum tolerance dose or concentration, (MTD or MTC,
LD0 or LC0)=
The highest possible but still tolerable dose level with
respect to a pre-specified toxicity.
 no-observed-adverse-effect level (NOAEL)=
Greatest concentration or amount of a substance, found by
experiment or observation, which causes no detectable
adverse alteration of morphology, functional capacity,
growth, development, or life span of the target organism
under defined conditions of exposure.

 The Acceptable daily intake(ADI)= an estimate of the

amount of a chemical that can be ingested daily over a
lifetime without appreciable health risk.

Chapter 6 factors influencing toxic effects

• Factors influencing toxic effects
o Dose and concentration
o The chemical factors
o The host factors
o Exposure factors
o Environment factors
o Interaction of chemicals

Chapter 7 general toxicity

• Definition of LD50, MTD
LD50= a statistically derived dose of a substance that can be
expected to cause death in 50 percent of a given test population
exposed for a specified time.

MTD (maximum tolerable dose)= commonly estimated to be the

maximum dose that can be administered for the duration of a
specific study that will not compromise the survival of the
animals.

• Experimental design of acute of toxicity

Objectives:
(1) Give a quantitative estimate of acute toxicity, such as median
lethal dose(LD50) for comparison with other substances.
(2) Identify target organs and other clinical manifestations of
acute toxicity.
(3) Establish the reversibility of the toxic response.
(4) Provide dose-ranging guidance for other studies.

Selection of species of animal

 The species most often used are the mouse and rat, but
sometimes a non-rodent species is desirable.
 In the acute inhalation toxicity test and oral toxicity test,
rat and mouse are the primary species, and rat is the
preference. In dermal acute toxicity, the priority goes to
the albino rabbit.
 Healthy young adult animals are acclimatized to the
laboratory conditions for at least 5 days prior to the test
before the test animals are randomized and assigned to
the treatment groups.
 At least 5 rodents are used at each sex per dose level. If
females are used they should be nulliparous and non-
pregnant.

Route of administration
 Based on the way which human actually contact with the
toxicant.
 The oral administration, compounds can be administered
mixed in the diet, dissolved in drinking water, by gastric
gavage, or by gelatin capsules.
 Inhalation, conducted in inhalation exposure chambers.

Dosage and experimental groups

 A dose that would kill about half of the animals
 Another that would kill more than half
 A third dose that would kill less than half
 The precision of the LD50 is improved by increasing the
number of animal per dose and by decreasing the ratio
between successive doses.
 Generally 40-50 animals are used in each LD50 test and
ratios of 1.2-1.5 are selected.

Observation and examination

  The observation period is generally 14 days after
exposure.
 A careful clinical examination should be made at least once
each day.
 Observations should include changes in the skin and fur,
eyes and mucous membrances, and also respiratory,
circulatory, autonomic and central nervous system, and
behavior pattern.
 Particular attention should be directed to observation of
tremors, convulsion, salivation, diarrhea, lethargy, sleep
and coma.
 The time of death should be recorded as precisely as
possible.
 Animals which die during the test should be necropsied. If
necessary, at the end of the test the surviving animals are
sacrificed and necropsied.

Alternative methods of acute toxicity tests

• Reduce the number of test animals
• Refine procedures to make exposures less stressful to
animals

Chapter 8 Mutagenesis
• Types of mutation
 • Mechanisms of mutagenesis
 DNA as Target
• 1. as base analogs causes mismatch;
• 2. directly react DNA, causing structural changes;
• 3. indirectly react DNA, causing cell to synthesize
mutagens.

 DNA Not as Target

• Altering the chromosomal segregation.
• Disturbing the DNA synthesis and repair system.

 DNA repair
 Basic principles:
 Damage recognition, removal of damage
(except for stand breaks or cleavage of
pyrimidine dimers), repair DNA synthesis
and ligation.
 Undergo apoptosis, effectively releasing it
from becoming a mutant cell.
 Repair way:
 Direct repair, base excision repair,
nucleotide excision repair, double-strand
break repair and so on.

• Examples of Genetic Toxicology Assays

CHO = Chinese Hamster Ovary, HGPRT = hypoxanthine-guanine phosphoribosyl

transferase gene in CHO cells, SHE = Syrian Hamster Embryo, BALB = BALB/3T3
cell transformation assay, Comet = also called single cell gel electrophoresis
(SCGE)., DNA = deoxyribonucleic acid.
* ICH S2B assay
‡ Good correlation with carcinogenicity (see: Regul. Toxicol. Pharmacol. 44:83-96,

2006)
† Poor correlation with carcinogenicity (see: Regul. Toxicol. Pharmacol. 44:83-96,

2006)

Chapter 9 Chemical carcinogenesis

• What is carcinogenesis? Carcinogen?
Carcinogenesis: is the progress through which cancer develops.

Carcinogen: an agent, chemical or physical, that causes or

induces neoplasms. (significant increased incidence)

• The three stages of carcinogenesis?

 Initiation:
• A stable, heritable change. The stage is a rapid,
irreversible process——mutational event.
• Initiating agents
• Characteristics:
• Irreversibility;
• The initiated cell is not morphologically
identifiable;
• Occurrence of initiated cells could be
spontaneous;
• Dose-response does not exhibit a readily
measurable threshold;
• The initiation process requires cell division for
“fixation”

 Promotion:
• The selective clonal expansion of initiated cells to
produce a preneoplastic lesion.
• Promoting agents
• Characteristics:
• Reversible;
 • Dose-dependent, has threshold;
• Organ-specific effects. (phenobarbital)

 Progression:
• The conversion of benign preneoplastic lesions into
neoplastic cancer.
• DNA damage, chromosomal aberrations and
translocations, karyotypic instability.
• Progression agents
• Characteristics:
• Irreversible;
• Autonomous growth and/or lack of growth
control;
An accumulation of nonrandom chromosomal aberration and
karyotypic instablility——hallmarks of progression

• Genotoxic mechanisms of carcinogenesis?

Metabolic activation of chemical carcinogens
• Direct-acting carcinogens/ indirect-acting
carcinogens;
• Procarcinogens
• Parent carcinogen
• Proximate carcinogen
• Ultimate carcinogen

Damage by DNA Reactive Carcinogens

• Ultimate carcinogens are strong electrophiles;
• React with nucleophilic constituents in vivo, and
form covalent adducts.
• Targets: S, O and N atoms;
• Sources: DNA bases and phosphodiester backbone;
• Different electrophilic carcinogens display different
preferences for nucleophilic sites in DNA and
different spectra of damage.

Damage by DNA Reactive Carcinogens

Another modification of DNA is the hydroxylation of DNA bases.
Oxidative DNA damage is caused by free radical reactions.
Covalent adducts inhibit DNA methylation, causing single-strand
breaks in DNA, alteration of methionine pools, and inactivation
of the DNA methyltransferase responsible for methylation.
 DNA Repair or Disrepair
 The persistence of the adduct is a major
determination of the outcomes.
 Depends on repair ability of cell with altered DNA.
 Adduct is insufficient to carcinogenesis process to
proceed because of cell’s ability to recognize and
repair damaged DNA.
 Repair occur later than cell division or relatively
inefficient——lead to cancer-causing mutations.

Mutation and Carcinogenesis

 The accumulation of mutations in critical genes.
 Not a single gene, but the accumulation of sequential
critical mutations in relevant target genes within a
single cell.
 The mutations can be the result of imperfect DNA
replication/repair following DNA damage caused by
carcinogens.
 Several steps from mutation and carcinogenesis.
(Figure 9-2)

Chapter 10 and 20 reproductive toxicology

• Principles of developmental toxicology
Developmental toxicity is any morphological or functional
alteration caused by chemical or physical insult that interferes
with normal growth, homeostasis, development, differentiation,
and/or behavior. Teratology is a specialized area of embryology.
Wilson’s General Principles of Teratology(1959)
1. Susceptibility to teratogenesis depends on the genotype of
the conceptus and the manner in which this interacts with
environmental factors.
2. Susceptibility to teratogenic agents varies with the
developmental stage at the time of exposure.
3. Teratogenic agents act in specific ways (mechanisms) on
developing cells and tissues to initiate abnormal
embryogenesis (pathogenesis).
4. The final manifestations of abnormal development are
death, malformation, growth retardation, and functional
disorder.
 5. The access of adverse environmental influences to
developing tissue depends on the nature of the influences
(agent).
6. Manifestations of deviant development increase in degree
as dosage increases from the no-effect to the totally lethal
level.

• Critical periods of susceptibility and development

segmentation
See book page 318
• Segment I, II, III study

1. Segment I-Fertility and general reproductive performance

segment
 Usually uses rats (20 per group)
– Young males treated for 10 weeks prior to mating
(spermatogenesis period)
– Female rats treated for 2 weeks prior to mating (cover
three estrus cycles)
– Three dose levels (without signs of maternal toxicity)
 Route of administration is usually based on the way which
human actually contact with the toxicant. But injection
is not suitable.
 Segment I endpoints
 Mating index = % of animals that are mated
 Fertility index = % matings that result in pregnancy

– Many other possible endpoints

 toxic effects on male reproductive system
 Gross pathology, histology

– Analysis of sperm-
 Sperm counts, sperm motility, sperm viability, sperm
morphology
 toxic effects on female reproductive system
 Gross pathology, histology

– Fertility index, stillbirth, number of implantation, estrus
cycles

2. Segment 2-Teratogenesis segment

 Usually two species: rabbits (12 per group) and rats (20
per group)
– Mated animals are treated during the period of
organogenesis (days 6-18 in rabbits, 6-15 in rats)
– Three dose levels
– Pups delivered by Caesarean one day before expected
parturition (21 days rat, 31 days rabbit)
– Uterus removed, weighed, and examined for
dead or
resorbed fetuses
– live pups are weighed, 1/2 examined for
skeletal
abnormalities, other half for soft tissue
abnormalities,
histology
– Information provided: embryotoxicity,
fetotoxicity,
teratogenicity
– gestation index = % pregnancies yielding live
litters

3. Segment III – Peri/postnatal segment

Usually one species (rats)
Pregnant females (20 per group)
2-3 dosages administered from end of organogenesis
period through delivery and lactation
Endpoints: birthweight, survival, growth during first 3
weeks of life, many others

 viability index = % animals surviving 4 days

– lactation index = % of animals alive at 4 days that survive
the 21 day lactation period
– Pup body weights pnd 4, 7, 14, and 21
– Gross necropsy and histopathology on some parents
(both reproductive and non-reproductive organs)

Chapter 11 Regulatory toxicology

• Terms: ADD/MOE/HQ
 • C: Concentration of the chemical in the contaminated environmental
medium to which the person is exposed.
• IR: Intake rate of the contaminated environmental medium.
• BW: Body weight of the exposed person.
• EF: Exposure frequency.
• ED: Exposure duration.
• AT: Average time.
• LT: Life time.

• Margin of Exposure (MOE):

MOE indicates the extent to which estimated exposure is
above or below the no-effect level.
Low risk is conveyed by high MOE.

• Hazard quotient (HQ):

HQ=ADD / RfD
The chance of toxicity increases as the HQ increases.

• Four steps process for risk assessment? (Figure 11-1)

HAZARD IDENTIFICATION,DOSE RESPONSE
ASSESSMENT,EXPOSURE ASSESSMENT,RISK
CHARACTERIZATION

Chapter 12 Blood toxicology

Mechanisms and Types of Toxic Action
 Alterations in Red Blood Cell Production:
• Interfere with steps in erythoblast heme synthesis
and result in sideroblastic anemia.
• The initial reaction of heme synthesis is the
mitochondria synthsis of ALA (δ-aminolevulinic
acid).
• Ferrochelatase (heme synthetase) catalyzes the
incorporation of ferrous iron into the
protoporphyrin IX.
 Denaturation of Hemoglobin and Hemolysis:
 • The heme irons of hemoglobin are susceptible to
chemical oxidation through the loss of an electron
with a valence change from 2+ to 3+. The resulting
pigment is called methemoglobin, and can not
combine reversibly with oxygen.
• Methemoglobinemia is one of possible causes of
anemic hypoxia.
 Preleukemias and leukemia:
 Alkylating agents used in cancer chemotherapy and
benzene can dysregulate hematopoiesis, resulting in
leukemogenesis.
 Cellular growth factors, protooncogenes, as well as
factors that govern survival, proliferation and
differentiation.
 Toxic Effects on Platelets and Coagulation System:
 Thrombocytopenia may be due to decreased production
or increased destruction.
 Thrombocytopenia is a clinically significant component
of idiosyncratic xenobiotic-induced aplastic anemia.

Main Cause of anemia

The three main causes of anemia are:

 Blood loss: Blood loss is the most common cause of

anemia, especially iron-deficiency anemia. Blood loss
can be short term or persist over time.

Heavy menstrual periods or bleeding in the digestive or

urinary tract can cause blood loss. Surgery, trauma, or
cancer also can cause blood loss.

If a lot of blood is lost, the body may lose enough red blood
cells to cause anemia.

 Lack of red blood cell production: Both acquired and

inherited conditions and factors can prevent your body
from making enough red blood cells. "Acquired" means
you aren't born with the condition, but you develop it.
"Inherited" means your parents passed the gene for the
condition on to you.
 Acquired conditions and factors that can lead to anemia
include poor diet, abnormal hormone levels, some chronic
(ongoing) diseases, and pregnancy.

 High rates of red blood cell destruction:

 Both acquired and inherited conditions and factors can

cause your body to destroy too many red blood cells.
One example of an acquired condition is an enlarged or
diseased spleen.
 The spleen is an organ that removes wornout red blood
cells from the body. If the spleen is enlarged or
diseased, it may remove more red blood cells than
normal, causing anemia.
 Examples of inherited conditions that can cause your
body to destroy too many red blood cells include sickle
cell anemia, thalassemias, and lack of certain enzymes.
These conditions create defects in the red blood cells
that cause them to die faster than healthy red blood
cells.
 Hemolytic anemia is another example of a condition in
which your body destroys too many red blood cells.
Inherited or acquired conditions or factors can cause
hemolytic anemia. Examples include immune disorders,
infections, certain medicines, or reactions to blood
transfusions.

Chapter 13 immunotoxicology
Innate immunity
• Innate immunity is a nonspecific and humoral response
that operates as the first line of defense against pathogens.
• It is considered to be antigen independent and occur
without prior exposure to antigens.
• Matural immunity arises from several mechanisms,
including physical barriers like skin and mucus,
biochemical barriers like complement and cells of the
innate immune response like NK, NKT, PMN and
macrophage cells.

Adaptive immunity
  Highly specific and increases in magnitude with
successive exposure to foreign substances. The
essential to the development of specific immunity is
recognition of immunogens and generation of
immunoglobulins and immune lymphocytes.
 Adaptive immunity is a highly specific, inducible,
discriminatory, and unforgetting T lymphocyte-
dependent response.
 The two key features that distinguish the acquired
from innate immunity response are specificity and
memory.
 Adaptive immunity may be further subdivided into
cell mediated immunity (CMI) and humoral
immunity.
 Humoral immunity is mediated by the
immunoglobins secreted by terminally differentiated
B cells, the plasma cells.
 In cell-mediated immunity, specialized cells rather
than antibodies are responsible for the destruction
of foreign cells.

Types of toxic action

1. immunosuppression
2. a hypersensitivity reaction(allergic responses)
3. autoimmunity

Types of hypersensitivity reaction

• Type 1: IgE mediated (Immediate type)
• Type 2: IgM, IgG, cytolysis of cells
• Type 3: IgM, IgG Immune complex
mediated
• Type 4: T-cell mediated (delayed-type)

Chapter 14 Toxicology of the liver

• Types of Toxic responses
Cell Death
Fatty liver(steatosis)
Cholestasis
Hepatitis
Cirrhosis
Idiosyncratic liver injury
 • The formation and the characteristics of cirrhosis.
Cirrhosis
 The end, often fatal, stage of chronic progressive liver
injury.
 Portal hypertension, internal hemorrhage, hepatic failure
 Characteristic:
 Accumulation of extensive amounts of fibrous tissue,
specifically collagen fibers, in response to direct injury
or to inflammation.
Irreversible, has a poor prognosis

Cirrhosis
 Liver injury or inflammation →
 excess fibers accumulation around central veins, portal
tracts or within the space of Disse →
 fibrotic scars formed, disrupting the architecture of the
liver →
 when fibrotic scars subdivide the remaining liver mass
into nodules of regenerating hepatocytes, fibrosis has
progressed to cirrhosis.
 Inactive HSCs, HSCs apoptosis, breakdown of ECM and
hepatocyte regeneration

The reasons for the susceptibility of the liver to chemical attack

1.Unique position within circulatory system
2.liver receive nearly 30% of cardiac output
3.high concentration of xenobiotic in the liver(CYP450
INDUCED)
4.bile formation concentrate xenobiotic
5.Lver has high concentration of binding sites
Chapter 15 toxicology of the kidney

 Structure of kidney

• The nephron includes the following compomnents:

• Glomerulus: is a complex capillary network that
mechanically performs filtering blood.
• Bowman’s capsule: filters blood.
• Proximal tubule: reabsorbs the water, salts, glucose, and
amino acids.
• Loop of Henle: exchange countercurrent, which maintains
the concentration gradient.
• Distal tubule: is a site of secretion of H ions, potassium,
and certain drugs.

 Susceptibility of the renal system

• High renal blood flow
• Concentration of chemicals in tubular fluid
• Activation of pro-toxicants.
• Although the kidneys constitute only 0.5 percent of total
body mass, they receive about 20 to 25 percent of the
resting cardiac output. Consequently, any drug or chemical
in the systemic ciuculation is delivered to these organs in
relatively high amounts.
• A nontoxic concentration of a chemical in the plasma may
reach toxic concentrations in the kidney.

 Sites and types of toxic responses of the kidney

 Glomerular injury

• The glomerulus is the initial site of chemical

exposure in the nephron, and a number of
nephrotoxicantss produce structural injury to
this segment.
• Cyclosporine, amphotericin B, and gentamicin
impair glomerular ultrafiltration without a
significant loss of structural integrity and
decreased GFR.
• Chemically induced glomerular injury also may
be mediated by extrarenal factors. Circulating
immune complexes may be trapped within the
glomeruli. Neutrophils and macrophages
commonly are observed within glomeruli in
membranous glomerulonephriris, and the local
release of cytokine and reactive oxygen species
may contribute to glomerular injury.
 Proximal tubular injury
 • Because of their active absorptive and secretory
activites, the proximal tubules often have higher
concerntrations of toxicants.
• The proximal tubule has a leaky epithelium that
favors the flux of compounds into proximal
tubular cells.
• Segmental differences in transport and
accumulation appear to play a significant role in
the onset and development of proximal tubular
toxicity associated with certain drugs such as
cisplatin.
• Therefore, the proximal tubule is the most
common site of toxicant induced renal injury.

 Loop of Henle/Distal Tubule/Collecting Duct injury

• Chemically-induced injury to the more distal

structures, compared to the proximal tubule, is an
infrequent occurrence.
• Functional abnormalities at these sites manifest
primarily as impaired concentrating ability
and/or acidification defects.
• Amphotericin B, cisplatin induce an ADH-resistant
polyuria, suggesting that the concentrating defect
occurs at the level of the medullary thick
ascending limb and/or the collecting duct.

 Papillary injury

• The initial target of abusive consumption of

analgesics is the medullary interstitial cells,
followed by degenerative changes in the
medullary capillaries, loops of Henle, and
collecting ducts. High papillary concentrations of
potential toxicants and inhibition of vasodilatory
prostaglandins compromise renal blood flow to
the renal medulla/papilla and result in tissue
ischemia.

Chapter 17 nervous system toxicology

 Structure of nervous system

 • The function of the nervous system is to receive
information about external and internal
environment, integrate the information, and then
coordinate a response appropriate to the
environmental stimulus. All of the other organ
systems of the body are controlled by the nervous
system, thus damage to this “master system” by
toxicants can have far-reaching and even
devastating effects.

 Common features of neurons

(1) Neurons are polarized cells.

(2) Typically the end of the neuron that receives
information in the form of neurotransmitter
stimulation from other neurons is highly branched
into a region known as the dendritic tree.
(3) The neuron is in close contact with other neurons
via specialized structures called synapses.
(4) The presynaptic neuron, releases
neurotransmitter into the gap, or cleft, between the
 two neurons. The postsynaptic neuron then
recognizes this chemical signal via receptors. The
arborizations of the dendritic tree converge on the
soma, the latter usually then gives off a single axon.
(5) Neurotransmission down an axon is in the form
of electrochemical signals.

 Types and mechanisms of toxic action

 Astrocyte-mediated neurotoxicity
The action of toxicants is associated with astrocytic
swelling and morphological changes.
 Excitotoxicity
Glutamate and certain other excitatory amino acids
can cause neurotoxic effexts of excessive signaling
within the CNS.
 Neurodegenerative disorders
MPTP, enters the dopaminergic neurons of the
substantia nigra, resulting in their marked
degeneration and deaths, and may lead to
Parkinson’s disease.
 Myelination
 Axonal degeneration
 Neuronal injury

Chapter 18 Cardiovascular toxicology

 What is sustained Hypertension?

A major complication of primary cardiovascular
diseases.

 How does it happen?

 Causes: an elevated vascular resistance in all organs.

Development:
1. It becomes a disease of the microvasculature,
particularly the arteriolar microvasculature.
2. The incidence of temporary or permanent closure
of small arterioles is increased and causes increased
resistance of the end organs.
 3. The vascular smooth muscle cells become
hypertrophied. The most predominant change is that
all vascular smooth cells are exceptionally
responsive to norepinephrine.

Types of toxic action

1. Myocardial degeneration and regeneration
2. Myocardial cell death and signaling pathways
Mitochondria control of cell generation
Death receptors and signaling pathways
3. Cardiac hypertrophy and heart failure
Adaptive and maladaptive responses
Hypertrophic signaling pathway
Transition from cardiac hypertrophy to HF

END