Transcript Bez tytułu slajdu

Toxicology
 is the study of the adverse
effects of chemicals on
living organisms. It is the
study
of
symptoms,
mechanisms, treatments
and
detection
of
poisoning, especially the
poisoning of people.
 A toxin is a poisonous
substance.
A lethal dose (LD)
 is an indication of the lethality of a given
substance. Because resistance varies from
one individual to another, the 'lethal dose'
represents a dose (usually recorded as dose
per kilogram of subject body weight) at
which a given percentage of subjects will
die.
LD50, LC50
 The most commonly-used lethality indicator
is the LD50 (lethal dose), a dose at which
50% of subjects will die.
 LC 50 (lethal concentration) refers to
gaseous toxins and it is the concentration of
a toxic substance that causes death of 50%
of exposed subjects after 14 days of
exposure.
 In pharmacology an effective dose is the amount
of drug that produces a therapeutic response in
50% of the people taking it.
 The therapeutic index, is a comparison of the
amount of a therapeutic agent that causes the
therapeutic effect to the amount that causes toxic
effects. A commonly used measure of therapeutic
index is the lethal dose of a drug for 50% of the
population (LD50) divided by the minimum
effective dose for 50% of the population (ED50) .
 Minimum
dose is the lowest dose of a
substance/therapeutic agent/poison that produces
any biological effect in the subject.
 Maximum dose is the highest dose of a
substance/therapeutic agent/poison that produces
biological effect in the subject.
 Therapeutic dose is the dose of a therapeutic
agent that produces maximal therapeutic effect
accompanied by minimum side effects.
No-observed-adverse-effect level
(NOAEL)
denotes the level of exposure of an organism, found
by experiment orobservation, at which there is no
biologically or statistically significant (e.g. alteration
ofmorphology, functional capacity,growth, development or
life span) increase in the frequency or severity of any
adverse effects in the exposed population when compared
to its appropriate control.
 Intoxicology it is specifically the highest tested dose or
concentration of a substance or agent (e.g. radiation), at
which no such adverse effect is found in exposed test
organisms where higher doses or concentrations resulted in
an adverse effect.
Classification of poisons:
1. irritating (ammonia)
2. causing asphyxation (carbon monoxide,
cyanide)
3. narcotic (morphine, cocaine)
4. cytoplasmic (lead, mercury, arsenic)
5. allergens.
Factors deciding about poisons’
harmfulness:
solubility (in water and fats)
taste, smell, colour
chemical structure
volatility ( intoxication at workplace most
often results from inhalation of toxic
gases, mists, fumes or simply from lack of
oxygen)
5. dispersion (size of particles).
1.
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3.
4.
What happens with a poison in
human body?
1. Absorption (intake).
2. Distribution (in body fluids, tissues).
3. Biotransformation (chemical changes in
kidneys and/or liver).
4. Elimination (the body gets rid of the
poison and its’metabolites eventually).
5. Some poisons accumulate in human body
and remain in the tissues for years (lead).
Routes of poisons’ inatke:
1. by inhalation
2. through the skin
3. via digestive tract
 Poisons are distributed throughout the
body with the blood and body fluids.
 Biotransformation
of poisons occurs
mainly in the liver and kidneys.
 Some toxins accumulate in human bodies,
for example:
1. lead accumulates in bones and teeth
2. dioxins accumulate in fatty tissue
Routes of elimination of poisons:
1. with urine
2. with faeces
3. with sweat
4. with exhaled gases
5. with breastmilk
Lead
 Lead is a naturally occurring bluish-gray metal
found in small amounts in the earth's crust. Lead
can be found in all parts of our environment.
Much of it comes from human activities including
burning fossil fuels, mining, and manufacturing.
Lead has many different uses. It is used in the
production of batteries, ammunition, metal
products (pipes), and devices to shield X-rays.
Because of health concerns, lead from gasoline,
paints and ceramic products, and pipe solder has
been dramatically reduced in recent years.
Lead poisoning
 Acute (abdominal colic, jaundice, liver
failure, haematologic disorders,
encephalopathy, coma)
 Chronic (haematologic disorders,
neurological symptoms, deposits of lead in
bones and teeth).
Lead poisoning
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A n 18-year-old nonsmoking man presented to the emergency department
with a 1-week history of diffuse, colicky abdominal pain. He had
had no change in his bowel or bladder function. He had worked in a battery recycling
factory for the past year. Examination revealed diffuse abdominal tenderness,
as well as a bluish line around the gums, known as Burton’s line. Results of
routine hematologic, liver-function, and kidney-function tests were normal. Ultrasonography
of the abdomen was unrevealing. The blood lead level was elevated at 81 ng
per deciliter (3.9 nmol per liter) (reference range, <10 ng per deciliter [0.5 nmol per
liter]). The patient was admitted to the hospital and started on chelation therapy
with penicillamine. He was discharged in 2 weeks, after the pain had subsided and the
blood lead level had declined; the Burton’s line had disappeared. He was counseled
regarding potential occupational exposure. In developing countries, occupational
exposure is the main cause of lead poisoning. Persons working at sites where batteries
or plastics are manufactured, at printing or recycling factories, or in the paint
or ceramics industries are at greatest risk. Preventing exposure is the most critical
intervention. In developing countries such as India that have a growing recycling
industry, education regarding the hazards of heavy-metal poisoning is important.
Burton’s Line
Basophilic stippling of erythrocytes in lead
poisoning
Types of drug addiction
(by WHO):
 morphine type (opiates,
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opioids-opium, morphine,
codeine)
alcohol and barbiturates
cocaine
cannabis indica
amphetamine (and other
anorexic drugs)
khat
psychedelics
inhaled stimulants (glue
sniffing for example)
Physical dependence
 refers to a state resulting from chronic use of a drug that
has produced tolerance and where negative physical
symptoms of withdrawal result from abrupt
discontinuation or dosage reduction. Physical dependence
can develop from low-dose therapeutic use of certain
medications such as benzodiazepines, opioids,
antiepileptics and antidepressants, as well as misuse of
recreational drugs such as alcohol, opioids and
benzodiazepines. The higher the dose used, the greater the
duration of use, and the earlier age use began are predictive
of worsened physical dependence and thus more severe
withdrawal syndromes.
Psychological dependence
 is defined as "dependence on a psychoactive substance for
the reinforcement it provides.„
 A person becomes dependent on something to help
alleviate specific emotions. Psychological dependence
begins after the first trial which a person then becomes
satisfied and the satisfaction increases with each use. This
constant feeling leads to psychological reinforcement
which eventually leads to dependence. Of the various
things that a person can be psychologically dependent on,
"opiates, benzodiazepines, barbiturates, alcohol, and
nicotine" are among them. Along with substances, people
can also become dependent on activities as well; such as
shopping, pornography, self-harm, and many more.
When to suspect drug addiction?
 convictions for crime- to buy drugs
 any
psychosis,
particularly
with
visual
hallucinations, elation, or mania
 unexplained nasal discharge (cocaine sniffing)
 the results of injections: marked veins, abscesses,
hepatitis, AIDS
 repeated requests for pain killers- with only
opiates being acceptable.
Drug tolerance
 is when a subject's reaction to a specific
drug and concentration of the drug is
progressively reduced, requiring an increase
in concentration to achieve the desired
effect.
Tachyphylaxis
 is a sudden onset drug tolerance which is
not dose dependent.
Withdrawal syndrome
 is a set of symptoms occurring
in discontinuation or dosage reduction of
some types of medications. The risk of a
discontinuation syndrome occurring
increases with dosage and length of use.
Alcohol withdrawal syndrome
 Symptoms:may vary from mild sleep
disturbances and mild anxiety to very
severe and life threatening including
delirium, particularly visual hallucinations
in severe cases and convulsions (which may
result in death).
Symptoms of withdrawal from
opiates
 chills (shivering), cramps, insomnia,
dizziness, flu-like symptoms, malaise,
headaches, itching, muscle and bone pain,
nausea, sweating, restless legs syndrome,
runny inflammed nose, sneezing,
tachycardia, tremors, vomiting, yawning.
Drugs commonly overused:
 pain killers
 sedatives
 stimulants.
Drugs commonly taken in
overdose
 salicylic acid (aspirin)-Increased respiratory rate,
rapid pulse, tinnitus (ringing in the ears), nausea,
vomiting and abdominal pain. Potentially fatal due
to severe disturbances in metabolism. May be
washed out up to 12 h after ingestion. Measure
blood salicylate levels.
 paracetamol (panadol, tylenol)-Severe liver damage
may be caused by as little as 20 tablets, liver failure
develops after 5-6 days. Potentially fatal if more
than 20 tablets taken. Initial levels of paracetamol in
the blood serum of >300mg/l or 100mg/l at 12 hours
are bad prognostic sign. Antidote: N- acetylcystein.
 benzodiazepins
(valium, librium)-Drowsiness,
ventilatory depression. Not fatal on their own, but
the airway is greatly at risk due to coma and
breathing will be very depressed. Muscle cramps,
anxiety, insomnia, and dizziness are among the
common side effects of withrawal from moderate
dose usage. Withrdawal seizures and delirium
occur usually in withdrawal from high dosage.
Withdrawal should be done gradually, often over
many months.
 tricyclic
antidepressants
(amitriptyline,
imipramine)-Cardiac arrhythmias, ventilatory
depression, convulsions and coma. A potentially
fatal overdose, though patients may be washed out
up to 12h after taking tablets. Cardiac monitoring
is required.
Barbiturates
 Barbiturates produce severe respiratory
depression and arrest , hypothermia, coma.
High potential for fatality.
Barbiturate intoxication
 Most deaths from barbitirate-induced coma
are caused by pulmonary complication
(atelactasis, edema, bronchopneumonia) or
renal
failure.
Hypoventilation
is
characteristic, and only ten times the full
sedative dose can cause severe poisoning.
This low toxic-therapeutic ratio is one
reason why
barbiturate use
(hence
barbiturate coma) is declining.
 Management of overdose-ABC of resuscitation
(airway, breathing, circulatuion). Take the patient
to hospital. A washuot usually has to be performed
within 6 hours of the overdose. The procedure
consists of passing a wide-bore tube which the
patient swallows into the stomach and then gently
syphoning water in and out of the stomach to
remove tablet debris.
 Medicines to induce vomiting (such as syrup of
ipecacuanha) are usually given to small children
who have accidentally taken some tablets in
mistake for sweets.
 Alcoholism-excessive drinking of alcohol (ethyl
alcohol-C2H5OH) which becomes addictive. It
causes harm in the patient’s health, work and
social life.
 Alcohol is rapidly absorbed into the bloodstream
when drunk. It is a source of energy, so any
carbohydrates taken at the same time are not used
by the body and are stored as fat. Alcohol is a
depressant , not a stimulant and affects the mental
faculties. after use of alcohol judgement and coordination are impaired. Violent behaviour often
appears. Injuries in this condition are often,
especially head injuries. Alcohol can greatly
confuse the picture of a person suffering from
head injury.
 The injury is further complicated by the
increased risk of vomiting . It is possible for
people to drink themselves into a coma,
vomit, and die from asphyxation as a result
of inhaling vomitus.
Alcohol and organ damage
liver- fatty liver (50%), hepatitis 80% progress to
cirrhosis; brain- cortical atrophy fits, falls,
neuropathies, Korsakoff’s and Wernicke’s
encephalopathy; gut- peptic ulcers and erosions,
varices,
pancreatitis;
marrowanaemia,
haemolysis; heart- arrhythmias, cardiomyopathy.
 Chronic alcohol abuse increases the risk for:
hepatocellular
carcinoma,
mesangial
IgA
glomerulonephritis, ischaemic heart disease,
avascular necrosis of the femoral head.
Methyl alcohol intoxication
 Ethanol
is the standard antidote for
methanol. It inhibits the conversion of
methanol to its toxic metabolite, formic acid
by alcohol dehydrogenase.
Glycol intoxication
 Ethylene glycol is widely used as antifreeze.
It causes CNS depression and renal toxicity
characterized by oxalate crystals in the
tubules. As in methanol poisoning, ethanol
is used as a competitive substance for
alcohol dehydrogenase to decrease the rate
of formation of toxic metabolites.
Opioids
 Opium- is an extract of the juice of the poppy,
Papaver somniferum, which has been used for
social and medical purposes for thousands of years
as an agent to produce euphoria, analgesia and
sleep, and to prevent diarrhoea. It is used in
preparation of codeine, morphine, papaverine and
heroin.The term opioid applies to any substance,
which produces morphine-like effects that are
antagonised by naloxone. The older term opiate is
more restrictive meaning morphine–like drugs
with a close structural similarity to morphine, thus
excluding peptides and many synthetic analogues.
Morphine
 Is an alkaloid made from opium. Effects of
morphine: analgesia (kills acute or chronic pain),
euphoria, respiratory depression, depression of
coughing reflex, nausea and vomiting, pupillary
constriction (pin-point pupils), increase in tone
and reduced motility in many parts of intestinal
system resulting in constipation, delay in gastric
emptying, retarded absorption of other drugs,
contraction of gall bladder, constriction of biliary
sphincter (do not use in biliary colic due to
gallstones), release of histamine what causes
utricaria
or
itching,
bronchoconstriction,
hypotension.
Morphine
 Tolerance (physical and psychological) and
dependence develop. Abstinence causes
withdrawal syndrome with irritability, loss
of weight, body shakes, agression, yawning,
pupillary dilatation, fever, sweating,
piloerection,
nausea,
diarrhoea
and
insomnia
Heroin
 or diacetylmorphine is produced from morphine
by acetylation of both hydroxyl groups. It is a
narcotic drug in a form of white powder.Its
duration of action (about 2 h) is shorter than that
of morphine. Heroin produces a euphoric effect
when injected intravenously. It can be also inhaled
or snorted. It requires progressively larger dose to
produce the same effect , which leads the user to
ever bigger demands and the risk of accidental
overdose. Symptoms of withdrawal: ‘cold turkey’nausea, vomiting, abdominal pain, rapid pulse,
headaches, sweating.
 Overdose may cause respiratory depression and
coma, death from respiratory arrest is a strong
possibility. Signs that should alert you to the
possibility of a narcotics overdose include
pinpoint pupils, coma in the absence of alcohol,
head injury or diabetes and evidence of injection
sites. The first priority is to clear the airway,
oxygenate the patient. Naloxone is a specific
antagonist to any narcotic (usually 4 mg i.v.).
 Piloerection, pupillary dilatation, sweating,
tachycardia, and blood pressure elevation are
frequently seen in heroin withdrawal. It starts
within 6 to12 hours of the last dose and is quite
unpleasant, but not life threatening.
Codeine
 or
3-methylmorphine
is
made
commercially from morphine. It is used as
an oral analgesic for mild types of pain. It
causes little or no euphoria, is rarely
addictive, inhibits cough reflex, often used
in cough mixtures.
Amphetamines and related drugspsychomotor stimulants
 Pharmacological effects:
 locomotor stimulation
 alertness and euphoria
 stereotyped behaviour
 anorexia.
Amphetamine
 It also causes a rise in blood pressure and
inhibition of gastrointestinal motility. In man,
amphetamine causes euphoria. Amphetamines
have been used to improve the performance of
soldiers, military pilots and others who need to
remain alert under extremely fatiguing conditions.
It has also been en vogue as a means of helping
students to concentrate before and during exams.
But it is likely that the improvement caused by
reduction of fatigue is offset by the mistakes of
over-confidence. Most amphetamines are excreted
in the urine, and are easily detected.
Tolerance and dependence
 if amphetamine is taken repeatedly over a course
of a few days, a state of ‘amphetamine psychosis’
may develop, which is almost indistinguishable
from an acute schizophrenia attack. Visual and
auditory hallucinations occur, accompanied by
paranoid symptoms and aggressive behaviour.
Repetitive stereotyped behaviour may develop
(e.g. polishing shoes). When the drug is stopped
after a few days, there is usually a period of deep
sleep, and on awakening the subject feels
extremely lethargic, depressed and anxious
(sometimes even suicidal), and is often very
hungry.
 Tolerance develops rapidly. Dependence
appears to be a consequence of the
unpleasant after-effect that it produces,
which leads to a desire for a repeat dose.
There is no clear-cut physical withdrawal
syndrome, such as occurs in opiates.
Cocaine
 is found in the South American shrub, coca. These
leaves are used for their stimulant properties by
natives of South America, particularly those living
at high altitude in the Andes. The effect of
cocaine is euphoria and increased motor
activity. With excessive dosage , tremors and
convulsions, followed by respiratory and
vasomotor depression , may occur. The peripherial
sympathomimetic actions lead to tachycardia,
vasoconstriction and an increase in blood pressure,
body temperature may increase.
Cocaine
 Cocaine produces no clear-cut physical
dependence, but tends to cause depression
and dysphoria following the initial stimulant
effect, which can result in a considerable
degree of psychological dependence.
Psychotomimetc drugs –
psychodelic or hallucinogenic
drugs
 They
affect thought, perception, and mood,
without causing marked psychomotor stimulation
or depression. Psychotomimetc drugs fall broadly
into two groups:
 -those with a chemical resemblance to known
neurotransmitters (catecholamines or serotonin)LSD, psilocin, bufotenin, mescaline
 -drugs unrelated to monoamine neurotransmitterscannabis, phencyclidine.
Plants containing hallucinogenic
substances (atropine) in Poland:
 hyoscyamus niger
 datura stramonium
 atropa belladonna
 psilocine (other hallucinogen) is present in
some mushrooms
Hyoscyamus niger
Atropa belladonna
Datura stramonium (angel's
trumpet plant )
Mydriasis in the garden
 A healthy 3-year old boy was
brought to our emergency
department because of an acutely
dilated right pupil, which
developed after he had played in
the garden. Half an hour before
presentation, his parents noticed he
had been crying. They reported no
fall and no ocular or head trauma.
The right eye showed no pupillary
light reflex and no accommodation.
Physical examination was
otherwise normal. A detailed
history revealed that he had
touched and held a flower from an
angel's trumpet plant and then
rubbed his right eye.
 Angel's trumpet, a member of the genus
brugmansia, is an ornamental plant from South
America that is increasingly found worldwide and
contains parasympatholytic alkaloids such as
scopolamine, hyoscyamine, and atropine. In cases
of sudden, unilateral, nonreactive mydriasis in
healthy children, exposure to angel's trumpet
should be suspected. Severe intoxication resulting
from ingestion can lead to hallucinations,
hyperthermia, convulsions, flaccid paralysis, and
death. In the absence of any other sign of toxicity,
we reassured the parents and discharged the child.
The mydriasis disappeared spontaneously within 3
days.
Lysergic acid (LSD)
 occurs in cereal fungus, ergot. It causes alteration
of perception, hallucinations-visual, auditory,
tactile -may become confused. Thought processes
tend to become illogical and disconnected, but
subjects generally retain insight into the fact that
their disturbance is drug-induced. Occasionally,
LSD produces a syndrome that is extremely
disturbing to the subject ( the ‘bad trip’), it may
produce homicide or suicide attempt. It can lead to
more persistent mental disorder with altered
perception and hallucinations for up to 3 weeks
after a single dose of LSD.
Lysergic acid (LSD)
 There are also reports of a persistent state
resembling paranoid schozophrenia, which
responds to antipsychotic drugs but may
recur later. This means that LSD must be
regarded as highly dangerous drug, far
removed from the image of peaceful ‘
experience
enhancers’
that
hippy
subculture of the 1960s so enthusiastically
espoused.
overdosage of LSD
 Pupillary
dilatation,
piloerection,
hyperthermia
and
tachycardia
(sympathomimetic effects) are common in
overdosage of LSD. Other symptoms
include dizziness, weakness, drowsiness,
nausea,
and
parasthesias.
The
hallucinogenic effects can last for hours and
are mainly visual.
Cannabis
 Extracts of a plant Cannabis sativa,
which grows freely in temperate
and tropical regions contain the
active
substance
tetrahydrocannabinol.
Marijuana is the name given to
the dried leaves and flower heads,
prepared as smoking mixture, while
hashish is the extracted resin. The
main subjective effects in man
consists of a feeling of relaxation
and well-being and a feeling of
sharpened sensory awareness with
sounds and sights seeming more
intense and fantastic. Cannabis also
increases appetite.
The main peripheral effects of
cannabis are:
 tachycardia
 vasodilatation, which is particularly marked on
scleral and conjunctival vessels, producing a
characteristic blood-shot appearance
 reduction of intraocular pressure
 inhibition of nausea and vomiting
 bronchodilatation.
 Tolerance to cannabis
occurs only to a minor
degree and physical dependence has not been
clearly demonstrated, though it appears that
habitual cannabis users experience feelings of
anxiety , depression and irritability when the drug
is suddenly withdrawn.
 Certain endocrine effects occur in man after use of
marijuana, notably a decrease in plasma
testosterone ( by 50%), and a reduction of sperm
count (in subjects smoking 10 or more marijuana
cigarettes per week).
 Cannabinoids are used as ani-emetic drugs
(decreasing nausea and vomiting).
 The most common therapeutic use of cannabis is
as an antiemetic during cancer chemiotherapy. It
might have some analgesic and anticonvulsant
properties. Its ability to lower intraocular pressure
has not been therapeutically useful in glaucoma
(an eye disease). However, all the possible
therapeutic effects of cannabis are accompanied
by psychoactive effects, which include impaired
cognition, and perception, prolonged reaction
time, and impaired memory and learning.
Katha edulis
 is a plant growing in
East Africa, used in
Muslim
countries
(where alcohol is
prohibited)
being
socially
accepted.
Effect –stimulant.
Glue sniffing
 is commoner in boys than girls. It causes
renal tubular acidosis, can lead to
rhabdomyolisis, if prolonged- may lead to
cerebellar degeneration.
Nicotine and tobacco
 Tobacco growing, chewing and smoking was
indigenous throughout the American sub-continent
and Australia at the time that European explorers
first visited these places and smoking spread
through Europe during the 16th century. Until the
latter half of the 19th century , tobacco was
smoked in pipes, and by men. Cigarette
manufacture began at the end of the 19th century
and now cigarettes account for more than 90% of
tobacco consumption. Cigarette smoking by
women only began after the First World War.
FAGESTRÖM’s TOLERANCE
TEST
 Is a diagnostic tool helping to assess how
deeply one is dependent on tobacco
smoking.
 An average cigarette contains about 0,8g of
tobacco and 9-17mg of nicotine, of which about
10% is absorbed by the smoker. Nicotine in
cigarette smoke is rapidly absorbed from the
lungs, but poorly from the mouth and
nasopharynx.
 An average cigarette, smoked over 10 minutes,
causes plasma nicotine concentrations to rise to
20-30 ng/ml.
 Rapid tachyphylaxis and dependence develop. A
physical withdrawal syndrome occurs with:
irritability, impaired performance of psychomotor
tasks, aggressiveness and sleep disturbance. It
disappears after 2-3 weeks; however, the craving
for cigarettes persists for much longer.
 Almost one third of people who have tried tobacco
become addicted. In comparison, about 15%
become addicted to alcohol. Heroin is also highly
addictive (23% of users become addicted), but
since so few people even try heroin, the addiction
rate in society as a whole is quite low (0,4%).
Harmful long-term effect of
smoking:
 cancer, particularly of the lung, but also of
the mouth, throat and oesophagus
 coronary heart disease, and other forms of
peripheral vascular disease
 chronic bronchitis
 effects in pregnancy-reduced birth weight,
increases perinatal mortality.
The causative agents
responsible for these effects are:
 tar and irritants
 nicotine
 carbon monoxide
 All in all there were about four thousand
different harmful substances identified in
tobacco smoke and tar.