Organs-Related Toxicity

(Season 1)

Sukamto S M
Neurotoxicity

2
Neurotoxicity
The ability of certain substances to damage either structure or function of
nervous system
Types of neurotoxicity

Normal

Neuronopathy Vulnerability
• There is no ability to
Myelinopathy regenerate (irreversible).
• The surface area of nervous
Axonopathy system is large.
Transmission
toxicity
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 Neurotoxicity
Neuronopathy
• Loss is permanent (irreversible)
• Doxorubicin
• Anticancer which is associated
with PNS injuries (dorsal root
ganglia and autonomic ganglia)
• Methyl mercury
• Antifungal agent & fat soluble
• Injures neurons of the cerebral
cortex and cerebellar cortex
• Organotin
• Plasticizers and antifungal agent
• Injures limbic-cerebral neurons
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Neurotoxicity
Axonopathy

– CNS effects  irreversible

– PNS effects  may be
reversible
– n-hexane and 2-hexanon
• Industrial use and glues
• Metabolized to 2,5 hexanedione
which is neurotoxicant
– Acrylamide
• Paper products
• Polyacrylamide gels
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Neurotoxicity
Myelinopathy
• Myelin provides electrical
insulation.
• Hexachlorophene
• Antiseptic & fat soluble
• Results in intramyelinic edema
(PNS and CNS)
• Lead
• Can be found in many sources,
such as paint.
• Results in demyelination in PNS
• It can also mimic the action of
calcium
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 Neurotoxicity
Neurotransmission Damage
 Neurotoxicants may
• Interrupt transmission
• Block transmission
• Increase transmission
 Sarin gas
• Inhibits disintegration of acetylcholine
• Cholinergic effects are lengthened
 Nicotin
• Acute and chronic poisoning
• Binds with nicotinic receptors in
ganglia and the neuromuscular junction
 Cocaine
• Enters CNS easily
• Blocks re-uptake of cathecolamines
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Ocular Toxicity

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Environmental and occupational exposure to toxic Ocular Toxicity
chemicals, gases, and vapors, as well as the side
effects of therapeutic drugs, frequently results in
The retina and the central visual system are
structural and functional alterations in the eye and
especially vulnerable to toxic insult.
the central visual system.
Cornea

Products at pH extremes <2.5 or >11.5 can cause severe

ocular damage and permanent loss of vision.
• ACIDS
Hydrofluoric acid, sulfurous acid, sulfuric acid, chromic acid,
hydrochloric acid, nitric acid, and acetic acid.
• ALKALIES
Ammonium hydroxide, sodium hydroxide, potassium Effects:
hydroxide, calcium hydroxide, and magnesium hydroxide.
• Opacification
• ORGANIC SOLVENTS • Vascularization
Ethanol, acetone, diethyl ether, and toluene • Ulceration
• Blindness
Lens
• Cataracts are decreases in the optical transparency of the lens that
ultimately can lead to functional visual disturbances.
• Risk factors are aging, diabetes, low antioxidant levels, and
exposure to a variety of environmental factors (UV & Vis light,
trauma, smoking, drugs, and chemicals).
• CORTICOSTEROIDS
o Topical and systemic treatments cause cataract
o Proposed mechanisms  The drugs disturb electrolyte balance and react
with crystalline protein in lens.
• LIGHT
o Lens absorbs light (mainly UV A ~ 320 – 400 nm)
o Absorption of light energy in the lens  fluoropores & pigments 
yellow-brown coloration of the lens.
• PHENOTHIAZINES
o The drugs are used mostly for schizophrenic patients.
o Phenothiazines react with melanin  photosensitive products 
deposition in the cornea and lens.
 Retina
• The mammalian retina is highly vulnerable to toxicant-induced structural
and/or functional damage as a result of:
1) The very high rate of oxidative mitochondrial metabolism
2) High susceptibility of the rods and cones to degeneration
• CHLOROQUINE – HYDR OXYCHLOROQUINE
o Irreversible loss of retinal function
o The drugs bind to melanin resulting in accumulation in retina
• DIGOXIN
o Photoreceptors are the target since they have many Na+/K+-ATPases which are digoxin site of
action.
• TAMOXIFEN
o Chronic use (180 to 240 mg per day for 2 years) can lead to axonal degeneration
• METHANOL
o Leads to retinal edema  blindness.
o This is caused by formaldehyde formation.
o Treated with ethanol since it has higher affinity to alcohol dehydrogenase.
Organs – Related Toxicity
(Season 2)

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Cardiotoxicity – Vascular Toxicity

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Cardiotoxicant &
Vasculotoxicant
Actions
• Interference of ion
homeostasis.
 Na+ K+ ATPase
 Na+ Channel blockade
 K+ Channel blockade
 Ca2+ Channel blockade
• Altered coronary blood flow.
o Coronary vasoconstriction
o Chronotropic agents
• Oxidative stress
• Organellar dysfunction
http://www.pathophys.org/wp-content/uploads/2013/10/ActionPotential.png
 Cardiac Glycoside Plants
• Cardiac glycosides are organic compounds containing a glycoside acting
on cardiac muscle.
• The glycosides (digitalis, digitoxin, digoxin and ouabain) are found as
secondary metabolites in several plants.

Digitalis purpurea Nerium oleander Strophanthus gratus

Digoxin Mechanism of Action
Endocrine Toxicity

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Hypothalamus –
Pituitary – Organs
• Hypothalamus produces releasing-
or inhibiting- hormones.
• Those hormones stimulate or inhibit
release of other hormones produced
by pituitary gland
• Finally, hormones produced by
pituitary play roles in related
organs.
• Toxicants can affect 1)
hypothalamus 2) pituitary 3)
endocrine glands in organs
• The effects can be at synthesis,
storage or release stages of the
hormones.
Adrenal Gland
• Reasons of adrenal gland vulnerability:
1. It contains large store of lipids used to steroid synthesis.
Many xenobiotics are lipophilic.
2. It has many enzymes capable of metabolizing
xenobiotics.

• Several drugs can produce toxic effects.

 Synthetic steroids  Cushing’s Syndrome
 Spironolactone  inhibits aldosterone
 ACE inhibitors  inhibit AT II synthesis
 Azole antifungals  inhibit cortisol synthesis

http://www.dovemed.com/uploads/images/shutterstock_108941693.max-1000x800_X04ZFxa.jpg
Spironolactone
 Thyroid Gland

• Iodine is needed to produce thyroid hormone and

supplied from outside.
• The deficiency of iodine will result in
• Thyroid hormones: hypothyroidism.
 Tetra-iodo-thyronine (T4)  more produced
• Overproduction of thyroid results in
 Tri-iodo-thyronine (T3)  more potent hyperthyroidism
https://www.endocrineweb.com/sites/default/files/imagecache/gallery-
large/wysiwyg_imageupload/48/2015/02/11/thryoidpituitary15533191_s.jpg https://jeffreysterlingmd.files.wordpress.com/2016/01/thyroid-dysfunctions-symptoms.jpg
 Thyroid Gland
• Several toxicants or drugs are
associated with disturbances of
thyroid gland.
Propylthiouracil (PTU) & sulfonamides
 inhibit iodine uptake
Excessive iodine and lithium  block
thyroid hormones release
CCB & Chlorinated hydrocarbons 
induce metabolism of the hormones

https://previews.123rf.com/images/rob3000/rob30001410/rob3000141000003/32558857-goiter-Stock-Vector-
thyroid-goiter-hypothyroidism.jpg
Reproductive Toxicity

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Reproductive toxicity
• Reproductive toxicity refers to any adverse effect
on any aspect of male or female sexual structure,
function, and lactation including effects on the
reproductive potential and viability of the
offspring.

• This concept may also include the following:

• Organ toxicity.

• Behavioral teratogenicity.

• Developmental toxicity. 25
Physiology of Reproductive System
CNS

(–) (–)
Hypothalamus

Releasing
hormone (GnRH)
Tropic hormones
Anterior pituitary
(FSH, LH) (–)
Target organ hormones
(testosterone, estrogen)
(+)
Target organs
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Mechanisms and Targets of Male & Female
Reproductive Toxicants

Effects on germ cells  Transquilizers, narcotics and social drugs

• Vinyl chloride • Inhibit hypothalamic – pituitary – ovarian
• Ethylnitrosourea axis function by inhibiting gonadotropin
• Actinomycin D secretion.
 Effects on ovaries and uterus
Effects on sperm quality & production
 Cyclophophamide
 Vinblastine
 Vincristine
 Ionizing radiation
 Tamoxifen and clomiphen
 Prolonged scrotal heating
 Effects on sexual behaviour
Effects on endocrine function  Oral contraceptives
Cimetidine  Drugs of abuses
Diethylstilbestrol
Ketoconazole 27
 Drugs Categories on Pregnancy
A
Generally acceptable. (multiple vitamins)
B
May be acceptable. (amoxicillin, acetaminophen)

C
Use with caution if benefits outweigh risks.
(fluoroquinolones, aspirin)

D
Use in LIFE-THREATENING emergencies when no safer
drug available. (tetracyclines, ACE inhibitors)

X
Do not use in pregnancy.
(thalidomide, oral contraceptives, statins)
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Dermatotoxicity
Assignment!!!

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TOXINS FROM PLANTS
& ANIMALS
SUKAMTO S M
Toxins from Animals
 Toxin vs Toxicant
• TOXICANT  A manufactured chemical (drugs, pesticides,
industrial chemicals, by-products
• TOXIN  Produced by an organism (algae, fungi, invertebrates,
vertebrates)

Toxicant  Any chemical, either natural or synthetic, producing bad effects to the living
organisms.
Toxin  Toxicant produced by living organisms
All toxins are toxicants; Not all toxicants are toxins
 Toxins from Animals
• Produced by the animals as either
protective or attacking mechanisms.
Toxin forms
• There are two types of animals
producing toxins. • Enzymes
• Passive toxin – producing animals • Peptide/protein possessing
(poisonous/hewan beracun)  neurotoxic or cardiotoxic
Pufferfish properties
• Active toxin – producing animals • Small molecules such as
(venomous/hewan berbisa)  Snake biogenic amines

Bee venom
Biogenic amines  Histamines
Enzymes  Phospholipase A2
Peptides  Mast cell degranulators
Venomous/Poisonous Mammals

Vampire bats (Desmodus rotundus)

• Hematophagous

• Thermoreception

• Toxic saliva with ANTICOAGULANT properties.

• Attack sleeping preys

• Pumping actions of saliva when licking wound

• Prey don’t die from the bat attack or venom contact

Venomous/Poisonous Mammals
Platypus (Ornithorhyncus anatinus)
• Males only and delivery of this COAGULANT venoms
via spurs.

• Crural system (proteases, enzymes and peptides)

• C-type natriuretic peptides (CNP)

• Potent toxin

• Increase cGMP

• Defense and competition for females

• Not lethal to human

Venomous/Poisonous Arthropods

• Bees

• Spiders

• Centipedes

• Scorpions

• Urticating caterpillars
Funnel web spider Centipede
• Produces delta-hexatoxins. • The venom contains:
• Repetitive firing and prolongation of • Histamine
action potential • 5-HT
• Excessive release of neurotransmitters • Phospholipase A
• Epinephrine • Cardiotoxic protein
• Acetylcholine
• Medications
• Medications
• Analgesic
• Antivenom (IgG from rabbit serum)
• Local anesthetic
• Anticholinergic agents (atropine)
• Antihistamine
Venomous/Poisonous Marine Animals
Pufferfish Sea Snake
• Produces tetrodotoxin • Produces neurotoxins & myotoxins.
concentrated in the liver, gonad • Peripheral paralysis
& skin. • Muscle necrosis
• Blocks diffusion of sodium • Hyperkalemia
through sodium channel. • Does not affect blood caogulation
• Depresses respiratory &
vasomotor centers in the brain. • Medications
• Antivenom
• Medications • Dialysis
• Activated charcoal (1-2 hours • Antihistamines
after ingestion)
• Steroid
• Cholinergic agents (Neostigmine)
Spines Prickles

Toxins from Plants

Aflatoxin Thorns
 Amatoxin

Amanita muscaria Amanita bisporigera Amanita phalloides

• Amatoxin is found in several Amanita species

• Amatoxin can attack many cells, while the effect on the liver and kidney will result in
fatalities (lethal dose is 0.1 mg/kg). Death after amatoxin ingestion is around 60%)
• Amatoxin is a potent INHIBITOR of RNA Polymerase II, a vital enzyme in the synthesis
of mRNA.
 Phases in Amatoxin Toxicity
Phase I
• First 24 hours. Nausea, vomiting, diarrhea and abdominal pain.

Phase II
• Temporary symptom resolution.
• Worsening hepatorenal function.

Phase III
• 3-5 days after ingestion, renal and hepatic failure.
• Multi organs failure, shock and death.
Treatments of GIT decontamination 
Amatoxin activated charcoal in early
stage of ingestion.
Intoxication
Sylimarin  It can competitively
antagonize toxin binding to liver cell
membrane receptors. It also acts as
hepatoprotective, antioxidant &
antiinflammatory.

Penicillin-G  reduces/inhibits liver

uptake of amatoxin. Dose 1 million
units/kg/day IV
Treatments of Amatoxin Intoxication
Dexamethasone can be administered to
patients who have inflammation
caused by amatoxin.

The use of antioxidant is very

important to handle bad effect of
amatoxin, especially in the liver.
Cocaine
Cocaine

• Synthesized from
Erythroxylon coca
Terima Kasih
CLINICAL TOXICOLOGY
SUKAMTO S M
SALICYLATES
COOH COONa

• Mechanism of toxicity OH OH

• Respiratory alkalosis
• Metabolic acidosis
• Hypoglycemia
COOCH3 COOH
• Dehydration
OH OCCH3H

• Treatment? O
CYANIDE

• Highly toxic chemical

• Mechanism of toxicity
• Antidotes
• Amyl nitrite
• Sodium nitrite
• Sodium thiosulfate
• Hydroxycobalamin?
ACETAMINOPHEN

• Mechanism of toxicity
• N-Acetyl-p-Quinone-Imine
(NAPQI)
• Combination with alcohol will
increase acetaminophen –
induced hepatotoxicity
• Antidote?
BENZODIAZEPINES

• Depressant
• Mechanism of toxicity
• Combination with other
depressants?
• Effects induced by depressants
overdose?
• Antidote?
CARISOPRODOL

• Mechanism of action?
• Mechanism of toxicity?
• Treatment?
IBUPROFEN

• Toxicity mechanism
• Prostaglandin
• Treatments?
 TUGAS
• SETIAP ORANG menuliskan RESUME dari ke-6 topik toksikan yang
memuat:
• Mekanisme toksisitas
• Penanganan dan antidot yang dapat diberikan
• RESUME diketik komputer dengan aturan
• Maksimal 3 halaman kertas A4 (di luar lembar sampul)
• Spasi 1.5
• Margin 4,4,3,3
• Times New Roman
• Dikumpul hardcopy paling lambat 19 Oktober 2017
• KERJA SENDIRI…!!!
THANK YOU