introduction of Poisoning, types of poison , Poison mechanism of action and their effects, botulism , organophosphorus mushroom, snake venom, introduction of malignant hyperthermia, pathophysiology of it and their mechanism of effects.

1. Poisoning
Hari Sharan Makaju
M.Sc. Clinical Biochemistry
PG Student

2. Poisoning
•Poisoning is contact with a substance that results in
toxicity.
•Symptoms vary, but certain common syndromes may
suggest particular classes of poisons.
•Diagnosis is primarily clinical
• but for some poisonings, blood and urine tests can help.
•Treatment is supportive for most poisonings
• specific antidotes are necessary for a few.

3. Poisoning
•Poisoning causes defect in neurotransmission.
• Botulism
• Mushroom poisoning
• Organophosphorous
• Snake venom
•Besides this there are also other the toxic substance
that can damage to the brain or peripheral nervous
system on exposure.
• Examples :
• Lead, Tetanus toxin, Mercury ,Glutamate and nitric
oxide.

4. Botulism
• Botulism is a paralytic disease caused by potent protein neurotoxins
elaborated by Clostridium botulinum.
• Illness begins with cranial nerve involvement, and progression
proceeds caudally to involve the extremities.
• Cases may be classified as
• (1) food-borne botulism, from ingestion of preformed toxin in food
contaminated with C. botulinum;
• (2) wound botulism, from toxin produced in wounds contaminated with the
organism
• (3) intestinal botulism, from ingestion of spores and production of toxin in
the intestine of infants (infant botulism) or adults.
• Botulinum toxin, because of its extraordinary potency, has long been
considered a threat as an agent of bioterrorism or biological warfare
• ETIOLOGIC AGENT
• C. botulinum, a species encompassing a heterogeneous group of
anaerobic gram-positive organisms that form subterminal spores, is
found in soil and marine environments throughout the world and
elaborates the most potent bacterial toxin known.
• Organisms of types A through G have been distinguished by the
antigenic specificities of their toxins;

5. • Foodborne botulism.
• Foodborne botulism should be suspected in
patients who present with an acute
gastrointestinal illness associated with
neurologic symptoms.
• Symptoms usually appear within 12-36 hours
following consumption of contaminated food
products.
• Wound botulism
• Patients with wound botulism typically have a
history of traumatic injury with wounds
that are contaminated with soil.
• Since 1994, the number of patients with
wound botulism who have a history of
chronic intravenous drug abuse has
increased dramatically
• Intestinal Botulism
• In intestinal botulism, toxin is produced in and
absorbed from the intestine after the
germination of ingested spores.
• Infant botulism is the most common form of
botulism.

6. Pathophysiology of
Botulinum toxin
Toxin-mediated blockade of
neuromuscular transmission
in cholinergic nerve fibers.
Toxins
Absorbed in GIT blood
peripheral neuromuscular
synapse.
• Presynaptic block
Acetylcholine release
Muscle paralysis
If botulism is not treated
promptly, death can occur due to
the paralysis of the respiratory
muscles

7. The target substrate and cleavage site of each
serotype of the toxin.

8. Diagnosis
• Diagnosis of botulism must be considered in patients with
symmetric descending paralysis who are afebrile and mentally
intact.
• The bulbar musculature is involved initially, but sensory findings
are absent and, early on, deep tendon reflexes remain intact.
• The demonstration of toxin in serum by bioassay in mice is
definitive
• but this test may be negative, particularly in wound and infant
botulism.
• The demonstration of the organism or its toxin in vomitus, gastric fluid, or
stool is strongly suggestive of the diagnosis
• because intestinal carriage is rare
• Other assays are being developed and remain experimental.

9. •Although botulinum toxin can cause severe and often
fatal illnesses
•A very mild dose of the purified forms of BoNT have
been known to yield therapeutic benefits against
many diseases including:
• Strabismus,
• chronic migraine
• overactive bladder
• and also used as an anti-ageing cosmetic agent

10. Mushroom poisoning
• Mushroom poisoning refers to harmful effects from ingestion
of toxic substances present in a mushroom.
• Numerous mushroom species cause toxicity when ingested.
• Symptoms vary by species.
• Identification of specific species is difficult, so treatment
usually is guided by symptoms.
• All toxic mushrooms cause vomiting and abdominal pain
• Generally, mushrooms that cause symptoms early (within 2
hours) are less dangerous than those that cause symptoms later
(usually after 6 hours).

11. Mushroom poisoning
• Early gastrointestinal (GI) symptoms
• Mushrooms that cause early GI symptoms cause gastroenteritis,
sometimes with headaches.
• Diarrhea is occasionally bloody.
• Symptoms usually resolve within 24 hours.
• Delayed GI symptoms
• Mushrooms that cause delayed GI symptoms include members of
the Amanita, Gyromitra, and Cortinarius genera.
• The most toxic Amanita mushroom causes 95% of mushroom poisoning
deaths.
• Initial gastroenteritis, which may occur 6 to 12 hours after ingestion, can be
severe; hypoglycemia can occur.
• Liver failure and sometimes renal failure develop.

12. Mushroom poisoning
• Early neurologic symptoms
• Mushrooms that cause early neurologic symptoms include
hallucinogenic mushrooms, which are usually ingested
recreationally because they contain psilocybin, a hallucinogen.
• Early muscarinic symptoms
• Mushrooms that cause early muscarinic symptoms include
members of the Inocybe and Clitocybe genera.
• Symptoms may include the SLUDGE syndrome ( Salivation,
Lacrimation, Urination, Defecation, Gastrointestinal Distress
and Emesis)
• Including bradycardia, diaphoresis, wheezing, and
fasciculations. Symptoms are usually mild, begin within 30
minutes, and resolve within 12 hours.

13. Mechanism of Mushroom poisoning
• Muscimol and ibotenic acid from the Amanita muscaria appear to act on
the neurotransmitter system
• Ibotenic acid mimic the activity of the excitatory neurotransmitter
glutamate.
• Ibotenic acid toxicity comes from activation of the NMDA receptors
• NMDA receptors are related to synaptic plasticity and work with
metabotropic glutamate receptors to establish long term
potentiation .
• The NMDA receptor functions properly by allowing Ca2+ ions to pass
through after activation at the receptor site.
• The binding of ibotenic acid allows excess Ca2+ into the system which
results in neuronal cell death.

14. Mechanism of
Mushroom poisoning
• Ca2+ also activates Ca2+ /Calmodulin Kinase which phosphorylates
multiple enzymes.
• The activated enzymes then begin producing reactive oxygen species
which damages surrounding tissue.
• The excess Ca2+ results in the enhancement of the mitochondrial
electron transport system which will further increase the number of
reactive oxygen species.
• Resulting symptoms of neural excitation include agitation, ataxia,
hallucinations, and mental status changes.

15. Mechanism of Mushroom poisoning
• Muscimol activates GABAA receptors on neurons.
• The GABA neurotransmitter system is one of the brain's major
inhibitory systems.
• Therefore, muscimol acts to inhibit the activity of neurons in the
brain.

16. Mechanism of Mushroom poisoning
• Psilocybin/Psilocin Mushrooms
• The chemical structure of psilocybin and psilocin is similar to the
neurotransmitter called serotonin.
• In fact, the primary effect of psilocin is on the receptors for serotonin.
• Psilocin stimulates serotonin receptors in the CNS.
• Psilocin has affinity for 5-HT1A, 5-HT2A, and 5-HT2C receptors.
• Activation of 5-HT2A receptors leads to increased cortical activity
via glutamatergic excitatory postsynaptic potentials
• Activation of 5-HT1A receptors results in the inhibition of pyramidal cell activity
• There is also evidence that psilocybin reduces the reuptake of
serotonin by neurons in the brain allowing this neurotransmitter more
time to act in the synapse.

17. how does the Magic Mushroom work?
• Psilocin binds to
the Serotonin
Receptors (5-
HT) present in deep
cortical layers
• increasing the
glutamate release
which then activates
AMPA and NMDA
receptors.
• This activation
ultimately leads to
the increased
expression of BDNF
(Brain-derived
neurotrophic factor).
Psilocybin binds to the Serotonin receptors in the brain, which is involved in mood,
appetite and sleep.
BDNF acts on neurons of Central nervous system and helps to
support the survival of existing neurons and stimulate the growth
and differentiation of new neurons and synapses.

18. Fig. The 5-HT2 receptor is coupled to Gq. Upon activation,Gq induces phospholipase C to
hydrolyze PIP2 to IP3 and DAG.IP3 leads to the release of claclium from intracellular sotre while
DAG leads to activation of PKC and the formation of Arachidonic acid.Arise in intracellular
calcium activates calmodulin which closes potassium channels.

19. Organophosphorus Poisoning
• OP compounds were the most common form of poisoning comprising
52% of total cases
• They were fist used as an agricultural insecticide
• Later as potential chemical warfare agents.

20. Organophosphorus Poisoning
• The toxic mechanism of OP compounds is based on the
irreversible inhibition of acetylcholinesterase
• due to phosphorylation of the active site of the enzyme.
• Leads to accumulation of acetylcholine
• And subsequent over-activation of cholinergic receptors at the
neuromuscular junctions and in the autonomic and central nervous
systems.
• The rate and degree of AChE inhibition differs according to the
structure of the OP compounds and the nature of their
metabolite.

22. Acute OP Poisoning

23. Tests of Prognostic Value
• Decreased Cholinesterase
• Hyperglycemia
• Neutrophilic leucocytosis
• Proteinuria / glycosuria
• Blood pH [acidosis]

24. Snake Venom
• Snake venoms are secretion of venomous snake which are synthesized
and stored in venomous gland.
• Snake venom is a combination of many different proteins, peptides and
enzymes and they are generally not dangerous when ingested.
Enzymes :
• Phospholipase A2
• Phosphodiesterase
• Phosphomonoesterases
• L-amino acid oxidase
• metalloproteinases
Proteins
Disintegrin
Ancrod
Coagulant components,
Cardiotoxins,
Cytotoxins and
Neurotoxins
Inorganic cations
sodium, potassium,
magnesium and small
amount of zinc, nickel,
cobalt, iron

25. Venom
Neurotoxins Eg.
Cobra
Hemotoxins Eg. Russel’s
viper
Cytotoxins Eg.
Rattle
snakes
25
Types of Venom
• Haemo-toxic venoms ------affects cardiovascular system
• Cytotoxic venoms ----targets specific cellular sites
• Neuro-toxic venoms -----harm nervous system of human body.
• Enzymes--- hydrolyze protein and membrane components which lead to tissue
necrosis and blood clotting

26. Local toxicities of venomous snakebite

27. Initial presynaptic and postsynaptic effect of
snake venom PLA2

28. Sceond stage effect of PLA2 on the NMJ:Multi-
component synaptic paralysis

29. synthesis of known and speculative pathway convergence.

30. Pathophysiology of Snake Venom
• The post-synaptically active neurotoxins present in the venoms of all elapid and
sea snakes
• bind with high affinity to the a subunits of the acetylcholine receptors
(nicotinic acetylcholine receptors (nAChRs), )at the neuromuscular
junction
• preventing the binding of acetylcholine (Ach)
• thus blocking neuromuscular transmission.
• The neuromuscular paralysis can be fatal, but if ventilatory support is provided
most victims will resume natural breathing within 12–24 hours

31. Pathophysiology of Snake Venom
• α -neurotoxins, that have a curare-like mechanism of action
• causing a reversible blockage of acetylcholine receptors
• Dendrotoxins (mambas)
• Inhibit neurotransmissions by blocking the exchange of positive and
negative ions across the neuronal membrane
• lead to no nerve impulse, thereby paralyzing the nerves.
• Fasciculins(some rattlesnakes , mambas)
• Attack cholinergic neurons (those that use ACh as a
transmitter) by destroying acetylcholinesterase (AChE).
• Acetylcholine , therefore, cannot be broken down and
stays in the receptor.
• Causes tetany (involuntary muscle contraction),
which can lead to death.

32. Clinical Manifestation (Systemic)
• Hypovolemia, hypotension, shock
• Cardiac ischaemia and arrhythmia
• Acute renal failure, consumption coagulopathy,
rhabdomyolysis, and direct nephrotoxicity causing
tubular necrosis
• Thrombotic and hemorrhagic complications

33. Therapeutic role of Anti-venom
Many toxins from snake venom are investigated and formulated into
drugs for the treatment of conditions such as cancer, hypertension and
thrombosis.
• Fibrinogenolytic and fibrinolytic activity
• Snake venom enzymes remove fibrinogen from the circulation
without converting it to fibrin.
• The drug Aggrastat (tirobifan) was developed from a compound in
the venom of the saw-scaled viper (Echiscarinatus), and is sued as
an antiplatelet drug
• Cardiotonic and antiarrythmic activity
• Shermann et al observed that Malayan pit viper venom has blood
thinning properties and could be effective in treating stroke
patients.
• Gomes et al identifies a non-protein micro molecular toxin from
the Indian cobra. This toxin possesses antiarrhythmic properties at
microgram level.

34. Therapeutic role of Anti-venom
• Anti-Cancer activity
• Calmette et al investigated the use of cobra venom in the
treatment of cancer in mice.
• In case of in vitro study, venom showed potent cytotoxic and
apoptogenic effect on human leukemic cells (U937/K562) by
reducing cell proliferation rate and produced morphological
alterations .
• Muscle depolarization & Hemolysis activity
• Cytotoxin or Cardiotoxin are polypeptide of 60-70 amino acid
residues long found in snakes of elapid family having various
pharmacological effects such as depolarization of muscles, and
hemolysis.

35. Lead poisoning
• Lead (Pb) is a highly toxic heavy metal occurring naturally in the
Earth’s crust.
• Lead poisoning in children is an important health problem,
accounting for 0.6% of the global burden of the disease
according to the World Health Organization.
• Lead has long been recognized as a developmental
neurotoxicant that can interfere with the developing brain
• resulting in functional impairment, lack of muscular co-
ordination etc.

36. Effects on neurotransmission
• Lead suppresses activity-associated Ca2+ dependent release of
acetylcholine, dopamine and amino acid neurotransmitters
• lead affects presynaptic Ca2+ channels involved in transmitter release
• by activating PKC, lead increases the pool of releasable vesicles
• Synaptosomal sodium/potassium ATPase was increased by lead while
calcium ATPase was inhibited.
• Lead also disrupts the activity of synaptotagmin I, a protein localized in the
synaptic terminal that appears to be important for transmitter release
• Lead also alters neurotransmitter receptors

37. Effects of Lead
• Lead, a systemic toxicant affecting virtually every organ
system
• primarily affects the central nervous system, particularly the
developing brain.
• The ability of lead to pass through the blood-brain barrier is
due in large part to its ability to substitute for calcium ions.
• Within the brain, lead-induced damage in the prefrontal
cerebral cortex, hippocampus, and cerebellum can
• lead to a variety of neurological disorders, such as brain damage,
mental retardation, behavioral problems, nerve damage, and
possibly Alzheimer’s disease, Parkinson’s disease, and
schizophrenia.

38. Mercury
• Mercury is capable of inducing CNS damage by migrating into the brain by
crossing the BBB.
• Mercury exists in a number of different compounds, though
methylmercury (MeHg+), dimethylmercury and diethylmercury are the only
significantly neurotoxic forms.
• Mercury exposure is mainly due to ingestion of contaminated fish with
methylmercury.
• Prevalence: 1-9 / 100 000
• It is known that the mercuric ion inhibits amino acid (AA) eg. glutamate
(Glu) transport, potentially leading to excitotoxic effects.

40. Malignant hyperthermia (MH)
• MH is a life-threatening clinical syndrome of hypermetabolism involving the
skeletal muscle.
• Triggered in susceptible individuals primarily by the volatile inhalational
anesthetic agents and the muscle relaxant succinylcholine
• as potential triggers
• MH is not an allergy but an inherited disorder that is found both in humans
and in swine
• In persons susceptible to MH, the ryanodine receptor in skeletal muscle is
abnormal, and this abnormality interferes with regulation of calcium in the
muscle.
• An abnormal ryanodine receptor that controls calcium release
• causes a buildup of calcium in skeletal muscle, resulting in a massive
metabolic reaction

41. Malignant hyperthermia (MH)
• In a large proportion (50–70%) of cases, the propensity for
malignant hyperthermia is
• due to a mutation of the ryanodine receptor (type 1),
• Ryanodine receptor located on the sarcoplasmic reticulum (SR),
the organelle within skeletal muscle cells that stores calcium.
• RYR1 opens in response to increases in intracellular Ca2+ level
mediated by L-type calcium channels,
• thereby resulting in a drastic increase in intracellular calcium
levels and muscle contraction.

42. Normal Physiology
• Acetylcholine released,
binds to receptors
• Action potential reaches T-
tubules
• Conformation change at
DHP is transmitted to RYR1
• Calcium released from SR,
muscle contracts
• Reuptake of calcium into SR
via calcium-ATPase pump,
terminates the muscle
contraction
• DHP = dihydropyrimidine
receptor
• RYR1 = ryanodine receptor
subtype

43. Pathophysiology
•Trigger agents induce
prolonged opening of RYR1
• Uncontrolled release of calcium →
continuous muscle activation
• Excessive stimulation of aerobic and
anaerobic metabolism→ metabolic
acidosis
• Increased oxygen consumption→
hypoxemia
• Increase in ATP usage → heat
production
• Depletion of ATP→ muscle rigidity,
rhabdomyolysis

44. Summary
• Poison or toxin can alter the activity of the nervous system in ways that
can disrupt or kill nerves, this effect is called as neurotoxicity.
• “Neurotoxicity" is the capacity of chemical, biologic, or physical agents to
cause adverse functional or structural change in the nervous system.
• Common examples of neurotoxins include lead, botulinum toxin,
glutamate and nitric oxide.
• Malignant hyperthermia is due to a mutation of the ryanodine
receptor(type 1)
• leads to metabolic acidosis, hypoxemia,heat production muscle rigidity,
rhabdomyolysis

46. References
• Ganong’s Review of Medical Physiology. 24th EDITION
• Harrison's principles of internal medicine. McGraw-Hill Professional
Publishing; 2018
• Michael R. Dobbs CLINICAL NEUROTOXICOLOGY: SYNDROMES, SUBSTANCES,
ENVIRONMENTS 2009
• Bacterial Toxins and the Nervous System: Neurotoxins and Multipotential
Toxins Interacting with Neuronal Cells.Michel R. Popoff and Bernard Poulain
• https://www.msdmanuals.com/professional/multimedia/table/v1031997
• http://thebrainssur.blogspot.com/2016/03/magic-shrooms-and-brain.html
• Paudyal BP, Organophosphorus Poisoning, jnma i vol 47 i no. 4 i issue 172 i
oct-dec, 2008
• Riyanka kantivan goswami, mayuri samant, rashmi s srivastava, snake venom,
anti-snake venom & potential of snake venom, Int J Pharm Pharm Sci, Vol 6,
Issue 5, 4-7
• Philip E. Bickler, Amplification of Snake Venom Toxicity by Endogenous
Signaling Pathways, Toxins 2020, 12, 68; doi:10.3390/toxins12020068
• https://emedicine.medscape.com/article/2231150-overview#a2
• Mary Frances Mullins, DNP, RN, CRNA, CPAN, CAPA ,Malignant Hyperthermia:
A Review Journal of PeriAnesthesia Nursing, 2017: pp 1-8