Pesticides: Organophosphates Dr. Bergfelt

Question 1

Would tetanus be considered a Ddx for organochlorine toxicity?

Answer 1

Yes!

Question 2

What are some important characteristics of Organophosphates (OP) to know

Answer 2

Irreversibly inactivates acetylcholinesterase (ACh)

Major cause of animal poisoning

Malathion is most common

Has various degrees of water & lipid solubility

Question 3

What are some chemical properties of OP

Answer 3

Thiophosphate OPs more lipid soluble than phosphate OPs

Subject to “storage activation” - If sealed & stored 1-2 years, more toxic they become!

Impurities = More toxicity - technical grade less pure than reagent grade

Question 4

Toxicokinetics of OP

Answer 4

Lipophilic - readily absorbed through skin & mucous membranes, GIT & inhalation

Well distributed including CNS

Tissue accumulation varies with type of OP - generally thiophosphates more lipophilic than phosphates

Extensively metabolized in liver - excretion/bioactivation

Lethal synthesis - CYP450 (liver enzymes) metabolize or bioactivate thiophospate OPs

Continued exposure can lead to adaptation to decr ACh

Question 5

Differences of types of OPs:

Answer 5

Phosphates (P=O) are biologically active

Thiophosphates (P=S) require hepatic bioactivation

Question 6

Thiophosphate OP particulars

Answer 6

Biologically inactive until transformed by liver to -oxon metabolites
Highly lipid soluble and rapidly absorbed in adipose tissue
Slow release from fat may lead to delayed and/or prolonged
cholinesterase inhibition
Slow redistribution or activation may have implications for
diagnosis and treatment
Major route of elimination is paraoxonase – a serum bound
enzyme

Question 7

MoA of OP

Answer 7

Irreversible inhibition of cholinesterases

High exposure can result in respiratory failure or paralysis & death

Delayed neurotoxicity is possible - OP induced delayed polyneuropathy

Question 8

Visual aid for MoA of OP

Answer 8

ACh accumulates throughout CNS resulting in overstimulation of muscarinic & nicotinic receptors

Question 9

Muscarinic effects of OPs

Answer 9

DUMBELS

Diarrhea

Urination

Miosis

Bronchospasm

Emesis

Lacrimation

Salivation

Question 10

Nicotinic effects of OPs

Answer 10

Acetylcholine accumulation at neuromuscular junction &
preganglionic synapses
initial stimulation→ fasciculations in muscle (incl
tongue) ⇒paralysis due to failure (blockade)
CS of stimulation →
sweating, hypertension and tachycardia

Question 11

CNS effects of OPs

Answer 11

Crosses BBB

Respiratory failure usual COD

Recovery depends ultimately on generation of new enzyme or ACh-esterase in critical tissues

Question 12

Delayed effects of OPs

Answer 12

OP-induced delayed polyneuropathy
10-14 days post exposure
CS - muscle weakness, ataxia, rear limb paralysis
Chickens are most sensitive
OP-induced intermediate syndrome
2-4 days after acute cholinergic effectand signs of the acute
effects are no longer obvious
CS occur after apparent recovery from the acute effects
NO muscarinic signs or muscle fasciculations
Weakness of respiratory muscles (diaphragm, intercostal) and accessory muscles, including neck muscles and of proximal limb muscles

Question 13

special MoA of OP

Answer 13

Ageing: conformational change in OP – Ach-esterase
complex that results in increased or irreversible binding
of the complex
Various aging times range from 2 min to 72 h depending on OP

Irreversible inhibition of cholinesterases
Non-competitive inhibition

Question 14

CS of OPs

Answer 14

Onset is rapid! 15min -1 hr

Question 15

Pathology of OP

Answer 15

Acute death, no specific lesions

Few nonspecific lesions

Delayd or intermediate effects: degeneration & demyelination of peripheral & spinal motor neurons

Question 16

Lab Dx of OP toxicity

Answer 16

Direct detection of presence of OP

for oral exposure: analysis of stomach or rumen contents

for dermal exposure: analysis of hair/skin

may find residues in fat/liver with OPs that are more lipophilic

Plasma acetylcholinesterase activity level (blood sample) - <50% activity = suspicious, <25% activity = diagnostic

Question 17

Clinical Dx of OP

Answer 17

Hx of exposure

PE

Atropine response test:

• If atropine + (means you see what you’d expect with a dose of atropine) then low likelihood of OP poisoning*
• If atropine - then high likelihood of OP poisoning*

Question 18

Tx of OP

Px

Answer 18

Acute tx:

Decontaminate, Supportive care

Avoid phenothiazines, aminoglycosides, muscle relaxants, drugs that depress respiration (opioids)

Atropine - specific physiologic antagonist

Cholinesterase reactivators - “oximes”

Pralidoxime or 2-PAM

may or may not be effective depending on OP and if ageing has occurred

OP induced delayed polyneuropathy:

symptomatic tx only

OP induced intermediate syndrome

supportive care

PX: GUARDED

presented alive w/ no CS Px = good

alive w/ mild-moderate CS = generally treatable

acute cases that respond to tx can recover in 24 hr

presented w/ multiple CS = depends on $