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PED3011 Toxicology > Organophosphates > Flashcards

Organophosphates Flashcards

1
Q

Describe the difference between herbicides, fungicides and pesticides

A

Herbicides: kill plants e.g glyphosate
Fungicides: stop fungal disease e.g triazole
Pesticides: harmful to pests

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2
Q

What are the benefits of pesticides

A

Improve/protect our health
Allow production of abundant, inexpensive and agricultural products

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3
Q

What are the risks of pesticides

A

Toxicity to non-target species
Pervasive in environment

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4
Q

How can we decrease the risks of pesticides

A

Use pesticides that have selective targets
Introduce regulations to reduce exposure

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5
Q

Describe insecticides

A

Neurotoxicants i.e act by targeting the insects nervous system
Cause hyperexcitabilty of NS = paralysis and death
Variety mechanisms of action
Generally non-selective so affect mammalian NS targets too

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6
Q

What is the target and effect of organophosphates as an insecticide

A

Acetylcholinesterases
Inhibition

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7
Q

Describe an organophosphate

A

Organic derivative of phosphates, phosphonates or phosphinates
Can be used as insecticides, lubricants, flame retardants and nerve agents

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8
Q

What does acute toxicity of organophosphates look like

A

0.5-6hrs after exposure
Tears
Salivation
Sweating
Bronchospasm
Bradycardia
Miosis

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9
Q

What part of the NS do organophosphates affect

A

Parasympathetic innervation
ACh and muscarinic receptors

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10
Q

What is the main cause of death after acute organophosphate poisoning

A

Respiratory failure
Parasympathetic bronchoconstriction and NMJ twitching
Paralysis of diaphragmatic muscles

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11
Q

What is an oxon

A

Insecticides have a phosphate-sulphur bond
When absorbed bioactivated to oxons during Phase I
P=S -> P=O
Inhibits AChEs

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12
Q

Why do nerve agents act quicker than other similar toxins

A

Already have P=O bond instead of P=S so don’t have to be bioactivated to cause effects

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13
Q

Describe how oxons cause acute toxicity

A

Normally ACh bind to AChE = weak bond that’s broken easily
Oxons target AChEs and phosphorylate them = strong bond between the 2
Can take hours/days to break bound therefore AChE is not free to hydrolyse ACh = build up

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14
Q

Describe detoxication of organophosphates

A

A-esterases such as PON1 can hydrolyse the Oxon = reactivated AChE
Hydrolysis produces excreted

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15
Q

How do polymorphisms affect detoxification of OPs

A

PON1 polymorphisms = different catalytic efficiencies towards OPs
-> some ethnicities are more affected by OPs

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16
Q

Describe ageing of OPs

A

Oxon binds to AChE and if one alkyl group is hydrolysed
= irreversible inhibited -> no detoxication

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17
Q

Can you overcome ageing of OPs

A

Yes only if the AChE function is restored by replenishing AChEs stores which can take days

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18
Q

What is a treatment for OP acute toxicity

A

Oximes
Atropine
Benzodiazepines

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19
Q

What is the mechanism of action of oxmines

A

Attaches to AChE and breaks the bond between P on oxon and AChE
= reactivated AChE

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20
Q

What is the main limiting factor to oxime treatment

A

Must be given within a relatively short amount of time after exposure to OPs
Before ageing occurs

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21
Q

Why is atropine useful in acute toxicity OP treatment

A

Muscarinic receptor antagonist = blocks the effect of excess ACh at the receptors
Relieves parasympathetic nervous system activation

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22
Q

How are benzo’s useful in acute OP toxicity

A

Allosteric modulators of GABAaR
= reduce the overstimulation of the neurones in the brain and act as anti-convulsants

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23
Q

What happens if treatment for acute OP toxicty is not administered

A

If the person hasn’t died from the toxicity intermediate syndrome can develop
Approx 24-96hrs post cholinergic crisis

24
Q

Describe intermediate syndrome

A

Weakness/ paralysis of muscles innervate by cranial nerves
Respiratory paralysis so need ventilation
May lead to death

25
Q

Why does recovery take up to 30 days after intermediate syndrome

A

Excess ACh is being removed from the synaptic clefts

26
Q

What is the proposed toxicological mechanism for intermediate syndrome

A

Nicotinic receptors overstimulated and become deactivated
Muscles are damage due to localised hyper contractions at the NMJ

27
Q

What is OP-induced delayed neuropathy

A

Loss of sensory or motor activation in the distal ends that is not related to nerve agents or insecticides
Develops 2-3 weeks after exposure

28
Q

What is axonopathy

A

Axon is affected and not related to the AChE inhibition

29
Q

Describe delayed neuropathy due to OPs

A

OPs target another esterase called neuropathy targeted esterase (NTE)
NTE found in neurones and important in membrane phospholipid homeostasis = affected axons

30
Q

What can low level repeated exposure to OPs lead to

A

Memory and attentional deficits
Increased risk of anxiety disorders and depression

31
Q

What is the effect on OPs on neuronal activity

A

Increases activity
Mediated by muscarinic and glutamate receptors

32
Q

Describe how oxons increase 5-HT

A

Increase neurotransmission via ACh
= increase glutamate release
= activates glutamate receptors on 5-HT neurones

33
Q

What is the suggested mechanism for why people exposed to OPs are at an increased risk of anxiety and depression

A

Decrease in inhibitory 5-HT1a receptor sensitivity
Decrease in 5-HT transporter
Increase in firing rate

34
Q

What are the 3 consequences to high level of OP toxicity

A

Acute/hypercholinergic toxicity
Intermediate syndrome
Delayed neuropathy

35
Q

What are carbamates

A

Derivatives of carbamic acid
AChE inhibitors

36
Q

Why are the effects of carbamates short lasting compared to OPs

A

Carbamylation of AChE is short lasting compared to phosphorylation by OPs
= rapid regeneration of AChE compared to inhibition by OPs

37
Q

What is the carbamate Physostigmine used for

A

Improve muscle tone in GI tract
Treat poor gut motility

38
Q

What is the carbamate Rivastigmine used for

A

Treatment in Alzheimer’s Disease
Improve cholinergic transmission in CNS
= compensates for neurodegeneration

39
Q

What are organochlorines

A

Organic compounds that contain at least one covalently bonded chlorine atom

40
Q

Why are organochlorines not easily metabolised

A

Very lipophilic and bioaccumulate in humans and animals and environment
= persistent organic pollutant

41
Q

Name 3 example of an organochlorine

A

Chlorinated ethane derivatives
Hexachlorocyclohexanes
Cyclodienes

42
Q

Describe acute toxicity after DDT exposure

A

Quite rare
Hypersensitivity of the mouth followed by ‘pins and needles’
Headaches, fatigue, tremor, muscle weakness and convulsion

CNS effects and often reversible

43
Q

Describe chronic low level exposure of DDT

A

Associated with psychological illness, peripheral neuropathy and Parkinsonism

44
Q

Describe the mechanism of action for chronic low level exposure from DDT

A

Increased excitability of CNS
= slow closures of Na+ channels so depolarising phase of AP is prolonged
= increased probably of repetitive firing

45
Q

Describe acute toxicity after exposure to hexachlorocyclohexanes and cyclodienes

A

Convulsions casued by increased excitability
Blocking of inhibitory GABAa receptor channel opening by binding to picrotoxin site

46
Q

How is acute toxicity after HCHs and cyclodienes treated

A

Diazepam

47
Q

What are pytherins and pyrethroids

A

Insecticides with higher insecticidal potency compared to mammalian potency = safer
Used in people’s homes

Pytherin: natural but decompose rapidly in the light
Pyrethoids: synthetic analogue of pytherins

48
Q

Describe acute toxicity after pyrethin or pyrethroid exposure

A

Tremor, seizures and death
Occupation exposures
Short lived

49
Q

How can pyrethroids be divided

A

Based upon toxic signs
Type 1 and Type 2

50
Q

Describe type 1 pyrethroids

A

Arousal, aggression and fine tremors

51
Q

Describe type 2 pyrethroids

A

Profuse salivation coarse tremors and convulsions

52
Q

What is the mechanism of action for type 1 pyrethroids

A

Stop the Na+ channels from causing causing respective firing

53
Q

What is the mechanism of action for type 2 pyrethroids

A

Keep the channels open longer
= depolarisation dependent block

54
Q

How can pyrethroids affect development

A

Exposure increases the risk of ADHD
Children with 3-PBA metabolite levels above limits of detection more likely to be diagnosed with ADHD

55
Q

What was the evidence in animal studies that supported epidemiological findings that pyrethroids have an affect of ADHD

A

Detrimental exposure to deltamethrin = increased transporter levels
-> decrease in extracellular DA levels
-> compensatory increase in D1 receptors
= increased activity and impulsive behaviour

PED3011 Toxicology (11 decks)

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