Transcript File

Lecture 1
th
14
March, 11
Toxicology
Introduction to Toxicology
What is toxicology
• Toxicology is the study of the
adverse effects of chemical or
physical agents on living
organisms.
Risk assessment
• Quantitative
estimate of the
potential effects on human health
and environmental significance of
various
types
of
chemical
exposures
(e.g.,
pesticide
residues on food, contaminants in
drinking water).
Graphical representation of the interconnections between
different areas of toxicology.
Different areas of toxicology
1. Mechanistic Toxicologist
• Identifying and understanding the cellular,
biochemical, and molecular mechanisms by
which chemicals exert toxic effects on living
organisms
• Mechanistic data (saccharin to cause
bladder cancer, thalidomide in leprosy and
AIDS, 6-mercaptopurine in leukemias)
• Relative toxic potential of organophosphate
insecticides
2. Descriptive toxicologist
• concerned directly with toxicity testing,
which provides information for safety
evaluation and regulatory requirements.
• Risk posed by a company chemical
(insecticides, herbicides, solvents) to
humans but also to animals
• Omics technologies
3. Regulatory toxicologists
• Responsibility for deciding, on the basis of
data provided by descriptive and
mechanistic toxicologists, whether a drug
poses a sufficiently low risk to be
marketed for a stated purpose or
subsequent human or environmental
exposure resulting from its use.
•
•
•
•
Food and Drug Administration
Federal Food, Drug and Cosmetic Act
Environmental Protection Agency
Federal Insecticide, Fungicide and Rodenticide
Act
General characteristics of
toxic response
• LD 50
• Microgram doses
• Physical state (gas, dust, liquids)
• chemical structure (aromatic amines,
halogenated hydrocarbons)
• Poisoning potential (slight………extreme)
• MOA (alkylating agent, cholinesterase
inhibitors)
Lecture 2
th
14
March, 11
Toxicology
Principles of Toxicology
Spectrum of undesired
effects
• Some effects deleterious others not
• Some side effects……others indication
• Diphenhydramine
(1st
generation
antihistamine”benadryl”) effective against
allergies but produces CNS drwsiness as it
crosses BBB. Often used as sleep remedy
e.g. tylenol PM
• Sometimes undesirable effects also
reffered to as deleterious effects
Allergic reactions
• For given allergic individuals the allergic
reaction are dose dependent
• Pattern of allergic response (in humans
skin and eyes and in guinae pigs bronchial
constriction)
• Anaphylactic shock
• Hapten-protein complex required time for
eliciting the formation of antibodies
• Time dependent
• Idiosyncratic
• Immediate vs delayed toxicity
• Local vs systemic
• Reversible vs irreversible
Idiosyncratic reactions
• Chemical
idiosyncrasy refers to a
genetically determined abnormal reactivity
to a chemical
• A classic example of an idiosyncratic
reaction is provided by patients who
exhibit prolonged muscular relaxation and
apnea (inability to breathe) lasting several
hours after a standard dose of
succinylcholine.
• Patients exhibiting this reaction have
genetic polymorphism in the gene for the
enzyme butyrylcholinesterase
Immediate vs delayed txicity
• Immediate toxic effects can be defined as
those that occur or develop rapidly after a
single administration of a substance,
whereas delayed toxic effects are those
that occur after the lapse of some time.
• Carcinogenic effects of chemicals usually
have a long latency period, often 20 to 30
years after the initial exposure, before
tumors are observed in humans.
• e.g Diethylstilbestrol (DES) during
pregnancy have a greatly increased risk of
developing vaginal cancer, but not other
types of cancer, in young adulthood, some
20 to 30 years after their in utero
exposure to DES
Reversible vs irreversible toxic
effects
• Some toxic effects of chemicals are
reversible, and others are irreversible.
• For example tissue injury of liver nad
tissue injury of CNS
Local vs systemic effects
• Chlorine gas reacts with lung tissue at the
site of contact, causing damage and
swelling of the tissue, with possibly fatal
consequences, even though very little of
the chemical is absorbed into the
bloodstream. (local)
• Tetraethyl lead produces effects on skin at
the site of absorption and then is
transported systemically to produce its
typical effects on the CNS and other
organs.
Lecture 3
th
18
March, 11
Toxicology
Principles of Toxicology
Interactions of chemicals
• Additive (2+3=5)
• Synergistic (2+2=20) e.g. carbon
tetrachloride + ethanol leads to
hepatotoxicity
• Potentiative (0+2=10) e.g. isopropranolol
+ ethanol
• Antagonistic (4+6=8) e.g. barbiturates
and vasopressor
Tolerance
• State of decreased responsiveness to a
toxic effect of a chemical resulting from
prior exposure to that chemical or to a
structurally related chemical. E.g. carbon
tetrachloride and cadmium, penicillins and
cephalosporins
Potential stages in the development of toxicity after chemical exposure.
Potential stages in the
development of toxicity
• Puffer fish poison (tetrodotoxin) ingestion
and reaches the voltage gated Na+ channels
of motor neurons, interaction with target
ions, result in blockade of channels,
inhibition of the activity of motor neurons
& ultimately skeletal muscle paralysis (no
repair for such toxicity).
• 2,4-dinitrophenol’s
entrance
in
mitochondrial matrix space, collapsing
directly outward across the inner
membrane
causing
mitochondrial
dysfunction
and
manifested
by
hyperthermia and seizures
The process of toxicant delivery is the first step in the development
of toxicity
Delivery of toxicant
• Gastrointestinal transporters
(monocarboxylate transporters for
salicylates, valporates and peptide
transporters for β-lactam antibiotics and
ACE inhibitors)
• Rate of absorption
• Conc.of chemical
• Thickness of stratum corneum
• Physiochemical properties e.g. lipid
solubility
• Epithelial circulation
• First pass effect e.g. oxidation of ethanol
by alcohol dehydrogenase in gastric
mucosa and enterohepatic circulation of
cyclosporine by P-glycoprotein transporter
and hydroxylation by CYP450.
• Distribution towards target mediated by
transporters
e.g.
monocarboxylate
transporters, peptide transporters, Pglycoprotein transporters, dopaminergic
transporters.
• Distribution away from target is facilitated
by BBB, binding to plasma proteins,
distribution in storage tissues like lead in
bone and of lipophilic drugs in adipose
tissue
Absorption
• Gastrointestinal transporters
(monocarboxylate transporters for
salicylates, valporates and peptide
transporters for β-lactam antibiotics and
ACE inhibitors)
• Rate of absorption and Conc.of chemical
• Thickness of stratum corneum
• Physiochemical properties e.g. lipid
solubility
• Epithelial circulation
Pre-systemic Elimination
• First pass effect e.g. oxidation of ethanol
by alcohol dehydrogenase in gastric
mucosa and enterohepatic circulation of
cyclosporine by P-glycoprotein transporter
and hydroxylation by CYP450.
Distribution towards and away
from Target
• Distribution towards target mediated by
transporters
e.g.
monocarboxylate
transporters, peptide transporters, Pglycoprotein transporters, dopaminergic
transporters.
• Distribution away from target is facilitated
by BBB, binding to plasma proteins,
distribution in storage tissues like lead in
bone and of lipophilic drugs in adipose
tissue
Excretion
• Excretion of drugs from blood to external
environment
• Renal transporters SLC family for diffusion
of ions and smaller molecule < 300 Da
• Excretion on the basis of lipid contents
and acidity
• Highly hydrophillic, organic acids and
bases efficiently removed by liver and
kidney
• Highly non volatile and highly lipophilic
eliminate slowly and tend to accumulate
• Gases and volatile liquids liquids diffuse
from pulmonary capillaries into the alveoli
and are exhaled
Reabsorption
• Toxicants delivered into the renal
tubules may diffuse back across the
tubular cells into the peritubular
capillaries.
• This process is facilitated by tubular
fluid reabsorption, which increases
the intratubular concentration as well
as the residence time of the chemical
by slowing urine flow.
• For organic acids and bases, diffusion is
inversely related to the extent of
ionization,because
the
nonionized
molecule is more lipid-soluble.
• The ionization of weak organic acids, such
as salicylic acid and phenobarbital, and
bases,
such
as
amphetamine,
procainamide, and quinidine, is strongly
pH-dependent in the physiologic range.
Toxication
• A number of xenobiotics (e.g., strong
acids
and
bases,
nicotine,
aminoglycosides,
ethylene
oxide,
methylisocyanate,heavy-metal ions ) are
directly toxic, whereas the toxicity of
others is due largely to metabolites.
• Biotransformation to harmful products is
called toxication or metabolic activation.
• With some xenobiotics, toxication confers
physicochemical properties that adversely
alter the microenvironment of biological
processes or structures.
• For example, oxalic acid formed from
ethylene glycol may cause acidosis and
hypocalcaemia as well as obstruction of
renal tubules by precipitation as calcium
oxalate.
Reaction of the ultimate toxicant with the target molecule: the second step in
the development of toxicity
Alteration of the regulatory or maintenance function of the cell: third first
step in the development of toxicity
Lecture 4
st
21
March, 11
Toxicology
Adverse Drug Reactions
Adverse Drug Reactions
• ADR’s
(definition
and
statistical
figures)
• Classification of ADR’s
• Type A and Type B reactions
(characteristics and types)
• Anaphylaxis (signs and symptoms,
diagnosis, management)
Lecture 5
25th March, 11
Toxicology
antidote : ATROPINE
ACTH
• Neurotransmitter in both the
peripheral nervous system (PNS) and
central nervous system (CNS)
• Ester of acetic acid and choline with
chemical formula
CH3COOCH2CH2N+(CH3)3
• Bethanechol, Melathione,Nicotine,
Pilocarpine, Suxamethonium
ACTH
• In
the peripheral nervous system,
acetylcholine activates muscles, and is a
major neurotransmitter in the autonomic
nervous system.
• In the central nervous system,
acetylcholine and the associated neurons
form a neurotransmitter system, the
cholinergic system, which tends to cause
anti-excitatory actions.
Atropine
• Therapeutic category
• Dosage forms
• Available brands
• Mechanism of action
Blocks the action
of
ACTH at
parasympathetic sites in smooth
muscles, secretory glands and heart.
Increases
cardiac
output,
dries
secretions, antagonizes histamine.
• Use
• Dosing
Organophosphate pesticides:
I/V 0.02-0.05 mg/kg every 10 to 20 minutes
until dry flushed skin, tachycardia and
mydriasis are observed then every 1-4
hours for at least 24 hours
Bradycardia:
I/V maximum total dose of 1 mg in children
and 2 mg in adolescents in repeated
doses.
• Monitoring parameters
Heart rate, blood pressure, pulse,
mental status, cardiac monitoring
• Adverse reactions
(palpitation, drowsiness, hallucinations,
urticaria, loss of taste, NVD, urinary
retention, blurred vision, pulmonary
edema, )
• Interactions
with drugs having anti cholinrgic
activities( phenothiazines and TCA’s)
• Overdosage treatment
Physostigmine 1-2 mg (children: 0.5
mg or 0.02 mg/kg) S/C or slow I/V
Lecture 6
28th March, 11
Toxicology
Antidote : DEFEROXAMINE
Iron poisoning
• Iron overload that leads to
ulceration in stomach then brain
and
liver
toxicity
following
metabolic acidosis.
• Treated by deferoxamine and
then dialysis
Aluminum poisoning
• Aluminum sources leads to colic, rickets,
GI disturbances, poor Ca metabolism,
extreme nervousness, anemia, headache,
decreased liver and kidney function,
forgetfulness, speech disturbances, and
memory loss, softening of the bones, and
weak, aching muscles
• Treated by chelation therapy
Deferoxamine
• Source (bacterial siderophore produced by
Streptomyces pilosus). Siderphores (iron
carriers) small, high-affinity iron chelating
compounds secreted by microorganisms
such as bacteria, fungi and grasses.
• Therapeutic category
• Dosage forms
• Available brands
• MOA
Complexes with trivalent ions (ferric ions) to
form ferrioxamine, which is removed by
the kidneys
• Use
Acute iron intoxication, diagnostic test for
iron overload, investigational use in the
treatment of aluminum accumulation in
renal failure
• Dosing
I/M 90 mg/kg/dose every 8 hrs;
maximum dose 6 g/day
OR
I/V 15 mg/kg/hr; maximum 6 gm/day
• Monitoring parameters
Serum ferritin, body weight. , B.P.,
ophthalmologic exams
• Adverse Reactions
Hypotension, seizures, dementia, urticaria,
dysuria, thrombocytopenia, leukopenia,
anaphylaxis
• Drug interactions
Vitamin C: concomitant usage can leads to
cardiac impairment
• Over dosage treatment
Symptomatic and supportive, dialysis
Lecture 7
1st April, 11
Toxicology
Antidote : FLUMAZENIL
Points to refresh . . . . . . . . .
• Neurotransmitter
• Synapse
• GABA receptors
• Hyper polarization (-ve membrane
potential )
• Benzodiazepines
BZD
enhance
the
effect
of
the
neurotransmitter (GABA), which results in
sedative,
hypnotic
(sleep-inducing),
anxiolytic (anti-anxiety), anticonvulsant,
muscle relaxant and amnesic action.
• Examples of BZD
Diazepam, alprazolam, Lorazepam
Flumazenil
• Therapeutic category:
Antidote, BZD antagonist
• Dosage forms:
Injection: 0.1mg/ml
Solution : 10 ml
• Available brands:
Inj. Anexate 0.1 mg/ml
ampoule)
(10
ml
Flumazenil
• Mode of Action:
Antagonizes the effects of BZD on the
GABA/BZD receptor complex.
• Uses:
BZD antagonist, reverse sedative
effects of BZD, used in general
anesthesia or conscious sedation
Flumazenil
• Dosing:
Management of BZD overdose:
Initial dose: 0.01 mg/kg (max. dose:
0.2 mg) with repeat doses of 0.01
mg/kg (max. dose: 0.2 mg) given
every minute to a maximal total
cumulative dose of 1 mg.
Flumazenil
• Monitoring parameters:
Level of consciousness and resedation
• Drug interactions:
Use with caution in mixed drug
overdose; especially with TCA’s
Flumazenil
• Over dosage treatment:
Maintain
airway/
ventilation as necessary
Administer I.V fluids
For seizures:
Diazepam, Phenytoin
support
Lecture 8
4th April, 11
Toxicology
Antidote : Penicillamine
Penicillamine
• Therapeutic category:
Antidote for copper and lead toxicity
Chelating agent
• Dosage forms:
Capsule: 250 mg ; Tablet : 250 mg
Solution : 10 ml
• Available brands:
Vistamine Tab 250 mg
Penicillamine
• Mode of Action:
Chelates with lead, copper, mercury,
iron and other heavy metals to form
stable, soluble complexes that are
ecreted in urine.
• Uses:
Cystinuria, Wilson’s disease, lead
poisoning
and
primary
biliary
cirrhosis.
Penicillamine
• Dosing
Lead poisoning:
20-30 mg/kg/day in 3-4 divided doses;
initiating treatment at 25% and maximum
dose: 1.5 g/day
Arsenic poisoning
100 mg/kg/day divided every 6 hrs for 5
days
Penicillamine
• Monitoring parameters:
CBC, hemoglobin, platelet count
• Interactions:
Food, antimalarials, gold
Lecture 9
15th April, 11
Toxicology
Oral Test
Lecture 10, 11 & 12
25th April, 11
Toxicology
Presentations
Lecture 13
29th April, 11
Toxicology
Arsenic toxicity
Arsenic toxicity
• King of Poisons, Arsenic trioxide, sodium
arsenite, arsenic acid, arsenilic acid &
arsenosugars.
• Arsine (AsH3) is an important gaseous
arsenical.
• Occupational exposure to arsenic occurs in
the manufacture of pesticides, herbicides,
and other agricultural products.
• Arsenic contaminated drinking water.
Arsenic toxicity
• Environmental exposure by burning of coal
containing naturally high levels of arsenic
and perhaps from wood reacted with
arsenical compounds.
• Food, especially seafood. Arsenic in
seafood is largely in an organic form called
arsenobetaine.
• Used as Fowler's solution in psoriasis
Arsenic toxicity
• Inhibits citric acid cycle by blocking lipoic
acid which is a cofactor for pyruvate
dehydrogenase; and also by competing
with phosphate and stops oxidative
phosphorylation, and thus inhibit energylinked reduction of NAD+, mitochondrial
respiration and ATP synthesis.
Arsenic toxicity
• Hydrogen peroxide production is also
increased, which might form ROS and
causes oxidative stress.
• These metabolic interferences lead to
death of multi-system organ failure,
probably from necrotic cell death, not
apoptosis.
• A post mortem reveals brick red coloured
mucosa, owing to severe haemorrhage.
Arsenic toxicity
• Skin is a potential route of exposure
presenting sign of white bands in
fingernails.
• Profuse sweating.
• UTI’s as indicator of urinary arsenic
toxicity.
• For acute arsenic poisoning, treatment is
symptomatic, with particular attention to
fluid volume replacement and support of
b.p.
• The oral chelator penicillamine.
• The best strategy for preventing chronic
arsenic poisoning is by reducing exposure.
Lecture 14
2nd May, 11
Toxicology
General Management of
Toxicity
General
Management
of
Toxicity
General Management of
Toxicity
• Antidotes exert a beneficial effect by;
Forming an inert complex with the poison
e.g. deferoxamine
Reducing the rate of conversion of the
poison to more toxic compound e.g.
ethanol
General Management of
Toxicity
Competing with toxic substances for
essential receptor sites e.g. oxygen,
naloxone, Vit. K.
Blocking essential receptors through
which the toxic responses are mediated
e.g. atropine
REDUCTION OF POISON ABSORPTION
INCREASED POISON ELIMINATION
Lecture 15
6th May, 11
Toxicology
REDUCTION OF POISON
ABSORPTION
Lecture 16
16th May, 11
Toxicology
Mid Term Paper discussion
Lecture 17
20th May, 11
Toxicology
Increasing Poison
Elimination
Increasing Poison Elimination
1. Urine alkalinization
• Unionized and lipid soluble molecules
•
are largely reabsorbed by the renal
tubules
With alkalinization drugs become
fully ionized and there is reduction in
reabsorption leading to enhanced
elimination.
Increasing Poison Elimination
• Alkalinization is achieved by incresing
urine pH to approximately 7.5 by
administering
I/V
sodium
bicarbonate.
Increasing Poison Elimination
2.
Multiple dose activated charcoal
administration
3. Haemodialysis
• In acute renal failure (ARF)
• In severe clinical features and high
plasma
concentration
of
ethanol,
methanol, lithium, isopropanol and
salicylates.
Some Physical Signs of Specific
Poisoning
• Constricted pupils
1. Opioids
2. Organophosphorus insecticides
• Convulsions
1. TCA’s
2. Opioids
3. Isoniazid
Some Physical Signs of Specific
Poisoning
• Dilated pupils
1. TCA’s
2. Antimuscarinic
• Dystonic reactions
1. Metoclopramide
2. Phenothiazines
Some Physical Signs of Specific
Poisoning
• Delirium and Hallucinations
1. Antimuscarinic drugs
• Loss of vision
1. Metahnol
2. Quinine
• Hypertonia
1. TCA’s
Some Physical Signs of Specific
Poisoning
• Papilloedema
1. Carbon monoxide
2. Methanol
• Nystagmus
1. Phenytoin
2. Carbamazapine
Some Physical Signs of Specific
Poisoning
• Tinnitus and deafness
1. Salicylates
2. Quinine
• Hyperthermia
1. MDMA (ecstasy)
Lecture 18
27th May, 11
Toxicology
antidote: NALOXONE
OPIOIDS
• An opioid is a chemical that works by
binding to opioid receptors, which are
found principally in the central and
peripheral nervous system and the
gastrointestinal tract.
• Obtained from opium plants.
• The analgesic effects of opioids are due to
decreased perception of pain, decreased
reaction to pain as well as increased pain
tolerance.
OPIOIDS
• Opioids
bind
receptors in the
other tissues.
principal classes
μ, κ, δ.
• Morphine,
Alfentanil
to specific opioid
nervous system and
There are three
of opioid receptors,
Mepiridine,
Fentanyl,
OPIOIDS
• The side effects of opioids include
sedation,
respiratory
depression,
constipation, and a strong subjective
sense of euphoria.
OPIOIDS
• Opioids can cause cough suppression,
which can be both an indication for
opioid
administration
or
an
unintended side effect.
• Opioid dependence can develop with
ongoing administration.
NALOXONE
Therapeutic category
• Antidote for narcotic agents
Dosage forms
• 400mcg/ml ampoule. (I.V, I.M, S.C)
Available brands
• Nalox Inj. 0.4 mg/ml
• Naloxone Inj. 0.4 mg/ml
Mechanism of Action
• Pure opioid antagonist that competes and
displaces narcotics at opioid receptor sites.
Uses/Indications
• Reverses CNS and respiratory depression
in suspected narcotics overdose;
• Neonatal opiate depression
Dosing
Opiate overdose:
• Adult (0.4-2mg/dose repeat every 2-3
minutes)
Post anesthesia narcotic reversal:
• Adult (0.1-0.2 mg direct I.V)
Monitoring parameters
• Respiratory rate
• Heart rate
• Blood pressure
Adverse Reactions:
• Cardiac arrest
• Hypertension
• Arrhythmias
Contraindications:
• Hypersensitivity to naloxone
Lecture 19
30th May, 11
Toxicology
Marine Toxicity
Ciguatera Fish Poisoning
• 4000
spp have been reported as
ciguatoxic (cigua mean toxic; used for
poisonous snail)
• Ciguatera is a foodborne illness caused
by eating certain reef fishes whose flesh is
contaminated
with
toxins
originally
produced by dinoflagellates
• Lipid soluble and heat stable compounds
• MOA: inhibition of acetyl cholinesterase
activity
Ciguatera Fish Poisoning
• Clinical features:
• The onset of symptoms occur from a few
minutes to 30 hrs. after ingestion of toxic
fish.
• Signs are: abdominal cramps, nausea,
vomiting, watery diarrhea, numbness and
parasthesias of lips, tongue and throat,
malaise, dty mouth, metallic taste,
myalgia,
arthralgia,
blurred
vision,
photophobia and transient blindness.
Ciguatera Fish Poisoning
• Recovery takes from 48 hrs to one week
in the mild form.
• Treatment:
Treatment is symptomatic although
atropine has occasionally lessened some
of the cardiovascular and gastrointestinal
manifestations.
Gabapentin may be useful in lessening
persistent parasthesias.
Ciguatera Fish Poisoning
• There is some evidence that calcium
channel blocker type drugs such as
Nifedipine and Verapamil are effective in
treating some of the symptoms that
remain after the initial sickness passes,
such as poor circulation and shooting
pains through the chest.
• Steroids and vitamin supplements support
the body's recovery rather than directly
reducing toxin effects.
Scombrotoxic Fish Poisoning
• This is due to the action of bacteria such
as
Proteus
morgani
and Klebsiella
pneumoniae in decomposing the flesh of
fish if the fish are stored at insufficiently
low temperatures.
• The spoiled fish can contain excessively
high conc of hiostamines (muscle histidine
is broken down by the bacteria to
histamine).
Scombrotoxic Fish Poisoning
• Clinical Features: The mean incubation
period is 30 minutes.
• The illness is characterized by flushing,
headache, sweating , dizziness, burning of
the mouth and throat, abdominal cramps,
nausea, vomiting and diarrhea.
Scombrotoxic Fish Poisoning
• Histamine
is an organic nitrogen
compound involved in local immune
responses
as
well
as
regulating
physiological function in the gut and
acting as a neurotransmitter. Histamine
triggers the inflammatory response.
Scombrotoxic Fish Poisoning
• Treatment:
Treatment is symptomatic
supportive.
Antihistami9nes
suppress the illness.
and
may
Stings from Marine animals
• Several spp of fish have venomous stings
in their fins.these include weaver fish,
short spine cottus, spiny dog fish and the
sting rays.
• Clinical Features:
• Intense local pain, swelling, bruising,
blistering, necrosis and if the poisonous
spine is not removed, chronic sepsis may
takes place.
Stings from Marine animals
• Treatment:
• Immersing the affected part in hot water
may relieve local symptoms as
denatures the thermo labile toxin.
this
Jelly Fish
• The stings of jelly fish contains a toxic
peptide phospholipase A and a hstamine
liberating factor.
• Clinical features: local pain occurs
followed by myalgia, nausea, gripping
abdominal pain, dyspnoea and even
death.
Jelly Fish
• Treatment:
Vinegar (3 to 10% aqueous acetic acid) is
a common remedy to help with jellyfish
stings
Adhesive tape my be used to remove any
tentacles still adherent to the patient.
Local analgesia and antihistamine creams
provide symtomatic relief.
Lecture 20
3rd June, 11
Toxicology
antidote: Protamine Sulfate
Heparin
• highly-sulfated
mucopolysaccharide, is
widely used as an injectable anticoagulant
• naturally-occurring anticoagulant produced
by basophils and mast cells
• pharmaceutically heparin is derived from
mucosal tissues of slaughtered meat
animals such as porcine (pig) intestine or
bovine (cow) lung
Heparin
• acts as an anticoagulant, preventing the
formation of clots and extension of
existing clots within the blood
• does not break down clots that have
already formed but allows the body's
natural clot lysis mechanisms to work
normally to break down clots that have
formed
Heparin
• Heparin and its low molecular weight
derivatives (e.g. enoxaparin, dalteparin,
tinzaparin) are effective at preventing
deep vein thromboses and pulmonary
emboli in patients at risk
• Heparin binds to the enzyme inhibitor
antithrombin
III
(AT)
causing
a
conformational change that results in its
activation through an increase in the
flexibility of its reactive site loop
Heparin
• The
activated AT then inactivates
thrombin and other proteases involved in
blood clotting, most notably factor Xa. The
rate of inactivation of these proteases by
AT can increase by up to 1000-fold due to
the binding of heparin.
Protamine Sulfate
Protamine Sulfate
Therapeutic category
• Antidote for heparin
Dosage forms
• Injection 10 mg/ml,
sulfate (5 ml, 25 ml)
solution
as
Protamine Sulfate
Mechanism of action
• Combines with strongly acidic heparin
to form a stable complex (salt)
neutralizing the anticoagulant activity
of drug.
Uses/Indications
• Treatment of heparin over dosage;
neutralize heparin during surgery or
dialysis procedures.
Protamine Sulfate
Dosing
• 1 mg of protamine neutralizes 90
units of heparin.
• Maximum of 50 mg in any 10 minute
period
Protamine Sulfate
Monitoring parameters
• Coagulation tests, APTT or ACT,
Cardiac monitor and blood pressure
monitoring
required
during
administration.
Protamine Sulfate
Adverse reactions
• Sudden fall in blood, hypotension,
hemorrhage,
dyspnea,
hypersensitivity reactions
Lecture 21
10th June, 11
Toxicology
Entomotoxicology
Entomotoxicology
• Entomotoxicology is the analysis of
toxins in arthropods (mainly flies and
beetles) that feed on carrion.
• Carrion refers to the carcass of a dead
animal.
• Using arthropods at a crime scene,
investigators can determine whether
toxins were present in a body at the time
of death.
Entomotoxicology
• This technique is a major advance in
forensics; previously, such determinations
were impossible in the case of severely
decomposed bodies devoid of intoxicated
tissue and bodily fluids.
Entomotoxicology
Techniques
1. Sample preparation
• Entomological samples are analyzed in
similar standards to human tissue
samples. Once the specimens have been
removed from the body, or the crime
scene, they are washed with deionized or
tap water.
Entomotoxicology
• The specimens are then frozen for storage
at a temperature ranging from -20°C to
4°C until they are needed for analyses.
• To prepare for analysis of inorganic
substances, the arthropods are taken out
of storage, washed, and then dried to
insure the removal of any foreign human
fluids.
Entomotoxicology
• The arthropods are then crushed and
stored in a porcelain crucible at a constant
650°C for 24 hours. The resulting ash has
a high concentration of metals, which are
then analyzed by acid digestion using 70%
HNO3 (nitric acid).
Entomotoxicology
• For preparation of organic substances,
the specimens are first washed and dried.
Between 1–10 grams of larvae are finely
cut and an internal standard solution is
added.
• The specimens are then homogenized, in
a 0.9% saline solution, and centrifuged.
Entomotoxicology
• Chitinous samples are prepared by adding
an internal standard solution to finely
chopped casings and placing the sample in
test tubes. Strong acids or bases break
down the chitinous exoskeleton to release
any toxins.
Entomotoxicology
• Hydrochloric acid is added to the test
tube, and the sample is allowed to extract
overnight at a temperature of 65°C.
• The acid solution is then removed and the
substances are fully available for further
analyses.
Entomotoxicology
2. Analysis
• Substances are analyzed using inductively
coupled plasma (ICP), atomic emission
spectroscopy (AES), and flame atomic
absorption spectrometry (FAAS).