Week terakhir tropmed

Organochlorides

It functions by opening sodium channels in the insect's nerve cells.[11] The contemporaneous rise of the
chemical industry facilitated large-scale production of DDT and related chlorinated hydrocarbons.

Organophosphates and carbamates

Carbamate insecticides have similar mechanisms to organophosphates, but have a much shorter
duration of action and are somewhat less toxic.[citation needed]

Neonicotinoids

Neonicotinoids are synthetic analogues of the natural insecticide nicotine (with much lower acute
mammalian toxicity and greater field persistence). These chemicals are acetylcholine receptor agonists.
They are broad-spectrum systemic insecticides, with rapid action (minutes-hours). They are applied as
sprays, drenches, seed and soil treatments. Treated insects exhibit leg tremors, rapid wing motion, stylet
withdrawal (aphids), disoriented movement, paralysis and death.[15] Imidacloprid may be the most
common. It has recently come under scrutiny for allegedly pernicious effects on honeybees[16] and its
potential to increase the susceptibility of rice to planthopper attacks.[17]

Ryanoids

Ryanoids are synthetic analogues with the same mode of action as ryanodine, a naturally occurring
insecticide extracted from Ryania speciosa (Flacourtiaceae). They bind to calcium channels in cardiac
and skeletal muscle, blocking nerve transmission. The first insecticide from this class to be registered
was Rynaxypyr, generic name chlorantraniliprole.[18]

Organophosphate

1. Mechanism intoxication clinical manifestations (organic phosphate intoxication clinical

manifestation)

• Organophosphates and carbamates are used extensively in the United States as insecticides. In
addition, interest in these substances has grown in recent years because of their association with
bioterrorism and potential for mass exposure.334 Organophosphates act as irreversible
acetylcholinesterase (AChE) inhibitors. Carbamates are reversible AChE inhibitors. Insecticides can be
absorbed through the mouth, skin, conjunctiva, gastrointestinal tract, or respiratory tract. Toxicity
occurs within 12 to 24 hours after exposure from excess acetylcholine at neural end plates due to
inhibition of AChE.335

• The diagnosis of organophosphate poisoning is made on clinical grounds and by measurement

of cholinesterase activity in the blood. The history may suggest attempted suicide, accidental ingestion,
industrial/agricultural exposure, terrorism, or rarely ingestion of contaminated food.336,337 Emergency
department personnel have also been inadvertently poisoned through contact with patients.338The
signs and symptoms of poisoning by both classes of insecticides are virtually identical except that
carbamates do not readily cross the blood-brain barrier to cause CNS toxicity. Clinical features include
miosis (85%), vomiting (58%), excessive salivation (58%), respiratory distress (48%), abdominal pain
(42%), depressed mental status (42%), and muscle fasciculations (40%).339 In one case series,
tachycardia occurred more often than bradycardia (21% vs 10% of cases). In early poisoning, there is a
transient period of intense sympathetic tone causing tachycardia, followed by heightened
parasympathetic tone and bradycardia, heart block, and ST- and T-wave abnormalities.338 Breath or
sweat may take on the odor of garlic.

• Clinical features of organophosphate poisoning result from overstimulation of muscarinic,

nicotinic, and central receptors (Table 124-25).340 Muscarinic overstimulation results in sustained
toxicity characterized by the mnemonic SLUDGE (salivation, lacrimation, urination, diarrhea,
gastrointestinal cramps, and emesis). Blurred vision, miosis, bradycardia, and wheezing are also
muscarinic effects. Nicotinic effects are less sustained and characterized by fasciculations, muscle
weakness (that can progress to paralysis), hypertension, and tachycardia. Organophosphates penetrate
the blood-brain barrier to cause anxiety, confusion, psychosis, seizures, and ataxia.

• The two principal cholinesterases are RBC cholinesterase (also called acetylcholinesterase or
AChE), which is present in red blood cells and nerve endings, and pseudocholinesterase (PChE), which is
found primarily in liver and serum. Carbamates and organophosphates inhibit both. Clinical toxicity is
due primarily to inhibition of AChE, but PChE is more readily quantified. Levels may not correlate with
the severity of poisoning.341 A falsely low PChE may be seen in liver disease, anemia, and malnutrition,
and as a normal genetic variant (familial succinylcholine sensitivity). Normal levels of enzyme activity do
not exclude poisoning because of wide variations in normal levels. In the absence of a baseline levels,
serial measurements may confirm the diagnosis.342

Carbamate insecticides

The carbamate insecticide Carbaryl.

The so-called carbamate insecticides feature the carbamate ester functional group. Included in this
group are aldicarb (Temik), carbofuran (Furadan), carbaryl (Sevin), ethienocarb, fenobucarb, oxamyl,
and methomyl. These insecticides kill insects by reversibly inactivating the enzyme
acetylcholinesterase.[2] The organophosphate pesticides also inhibit this enzyme, although irreversibly,
and cause a more severe form of cholinergic poisoning.[3]

Fenoxycarb has a carbamate group but acts as a juvenile hormone mimic, rather than inactivating
acetylcholinesterase.[4]

The insect repellent icaridin is a substituted carbamate.

Carbamate nerve agents

While the carbamate acetylcholinesterase inhibitors are commonly referred to as "carbamate

insecticides" due to their generally high selectivity for insect acetylcholinesterase enzymes over the
mammalian versions, the most potent compounds such as aldicarb and carbofuran are still capable of
inhibiting mammalian acetylcholinesterase enzymes at low enough concentrations that they pose a
significant risk of poisoning to humans, especially when used in large amounts for agricultural
applications. Other carbamate based acetylcholinesterase inhibitors are known with even higher toxicity
to humans, and some such as T-1123 and EA-3990 were investigated for potential military use as nerve
agents. However, since all compounds of this type have a quaternary ammonium group with a
permanent positive charge, they have poor blood-brain barrier penetration, and also are only stable as
crystalline salts or aqueous solutions, and so were not considered to have suitable properties for
weaponisation.[5][6]

Diagnosis

Organophosphate

Blood samples can measure plasma butyrylcholinesterase (pseudocholinesterase)

and red blood cell (RBC) AChE levels.37 Depressions of plasma pseudocholinesterase and/or RBC
acetylcholinersterase enzyme activities are generally available

biochemical indicators of excessive organophosphate absorption. Rarely, there have

been reports of cases of symptomatic organophosphate toxicity in which the initial

red blood cell cholinesterase levels were not depressed. Subsequent testing eventually demonstrated
depressed cholinesterase levels. Certain organophosphates may

selectively inhibit either plasma pseudocholinesterase or RBC acetylcholinesterase.38

A minimum amount of organophosphate must be absorbed to depress blood cholinesterase activities,

but enzyme activities, especially plasma pseudocholinesterase,

may be lowered by dosages considerably less than are required to cause symptomatic

poisoning. A 20%-30% depression of AChE may indicate a significant OP poisoning

that, even without symptoms, needs antidotal treatment. In severe cases, the enzyme

is usually depressed by 80%-90% of normal levels. The latter group typically requires

significantly high doses of atropine.4,37 Enzyme depression is usually apparent within

a few minutes or hours of significant absorption of organophosphate. Depression of

the plasma enzyme generally persists several days to a few weeks; the RBC enzyme

activity may not reach its minimum for several days, and usually remains depressed

longer, sometimes 1-3 months, until new enzyme replaces that inactivated by organophosphate. Lower
limits of cholinesterase levels vary among laboratories and methods,

so clinicians should interpret levels based on the given reference ranges. Patients with

clinical signs of toxicity and accompanied by AChE levels depressed by 20%-50%

should be managed as outlined in the treatment section.

The alkyl phosphates and phenols to which organophosphates are hydrolyzed in

the body can often be detected in the urine during pesticide absorption and up to about

48 hours thereafter. These analyses are sometimes useful in identifying and quantifying

the actual pesticide to which workers have been exposed. Urinary alkyl phosphate and

phenol analyses can demonstrate organophosphate absorption at lower dosages than

those required to depress cholinesterase activities and at much lower dosages than

those required to produce symptoms and signs. Their presence may simply be a result

of organophosphates in the food chain. These metabolites are among the numerous

chemical metabolites measured in a U.S. sample via the National Health and Nutrition

Education Survey (NHANES) and can be found in CDC’s National Report on Human

Exposure to Environmental Chemicals.3

Treatment organophosphate

Ensure that a clear airway exists. Intubate the patient and aspirate the secretions

with a large bore suction device if necessary. Administer oxygen by mechanically

assisted pulmonary ventilation if respiration is depressed and keep patient on a

high FiO2. In severe poisonings, patients should be treated in an intensive care

unit setting.

2. Administer atropine sulfate intravenously, or intramuscularly if intravenous

injection is not possible. Remember that atropine can be administered through

an endotracheal tube if initial IV access is difficult to obtain. Depending on the

severity of poisoning, doses of atropine ranging from very low to as high as 300

mg per day or more may be required,40 or even continuous infusion.41, 42 (See

dosage on following page.)

The objective of atropine antidotal therapy is to antagonize the effects of excessive

concentrations of acetylcholine at end-organs having muscarinic receptors. Test Dosage of Atropine

• Adults: 1 mg

• Children under 12 years: 0.01 mg/kg

Maintain atropinization by repeated doses based on recurrence of symptoms

for 2–12 hours or longer depending on severity of poisoning. Crackles in the lung

bases usually indicate inadequate atropinization. Pulmonary improvement may

not parallel other signs of atropinization. Continuation of or return of cholinergic

signs indicates the need for more atropine.

• Pralidoxime (2-PAM) reverses nicotinic and muscarinic effects of organophosphate poisoning by

reactivating AChE and protecting the enzyme from further inhibition. In carbamate poisoning,
pralidoxime may not be needed because of the more rapid resolution of symptoms and reversible
nature of enzyme inhibition. It has historically been suggested that pralidoxime may enhance carbaryl
(or Sevin, a carbamate insecticide) toxicity,345 although current recommendations recognize the
difficulty oftentimes present in distinguishing carbamate and OP toxicity and therefore recommend
oxime therapy in addition to atropine as needed.334 To be effective, pralidoxime should be given within
the first 6 hours of poisoning (although treatment in the first 24-48 hours may still be effective), prior to
irreversible phosphorylation of cholinesterase (a process referred to as “aging”). After this critical
period, restoration of normal cholinesterase function requires regeneration of the enzyme, a process
that may take weeks to complete. Antimuscarinic effects allow for atropinization more quickly, and with
lower doses of atropine. The initial dose of pralidoxime is 1 to 2 g IV given over approximately 10 to 20
minutes. Clinical response should be evident within 30 minutes. If there is no improvement in
fasciculations or weakness, the dose may be repeated once. A continuous infusion is then administered
at a rate of 200 to 500 mg/h, titrated to achieve the desired effect. Continuous infusion of pralidoxime
may be necessary for over 24 hours, depending on the half-life and lipid solubility of the poison, after
which the dose may be gradually reduced and stopped while the patient is observed for signs of
recurrent muscle weakness.

muscarinic effect, cholinergic, etc. (SLUDGE, DUMBELS)

Diarrhoea, Urination, Miosis/ muscle weakness, Bronchorrhea, Bradycardia, Emesis, Lacrimation

Salivation/ sweating
 Table 473e-1. Differential Diagnosis of Poisoning Based on Physiologic state
Stimulated Depressed Discordant Normal
Sympathetics Sympatholytics Asphyxiants Nontoxic exposure
Sympathomimetics α1-Adrenergic Cytochrome oxidase Psychogenic illness
Ergot alkaloids antagonists inhibitors “Toxic time-bombs”
Methylxanthines α2-Adrenergic Inert gases Slow absorption
Monoamine oxidase agonists Irritant gases Anticholinergics
inhibitors ACE inhibitors Methemoglobin Carbamazepine
Thyroid hormones Angiotensin receptor inducers Concretion formers
Anticholinergics blockers Oxidative Extended-release phenytoin
Antihistamines Antipsychotics phosphorylation sodium capsules (Dilantin
Antiparkinsonian β-Adrenergic inhibitors Kapseals)
agents blockers AGMA inducers Drug packets
Antipsychotics Calcium channel Alcohol Enteric-coated pills
Antispasmodics blockers (ketoacidosis) Diphenoxylate-atropine
Belladonna Cardiac glycosides Ethylene glycol (Lomotil)
alkaloids Cyclic Iron Opioids
Cyclic antidepressants Methanol Salicylates
antidepressants Cholinergics Salicylate Sustained-release pills
Mushrooms and Acetylcholinesterase Toluene Valproate
plants inhibitors CNS syndromes Slow distribution
Hallucinogens Muscarinic agonists Extrapyramidal Cardiac glycosides
Cannabinoids Nicotinic agonists reactions Lithium
(marijuana) Opioids Hydrocarbon Metals
LSD and analogues Analgesics inhalation Salicylate
Mescaline and GI antispasmodics Isoniazid Valproate
analogues Heroin Lithium Toxic metabolite
Mushrooms Sedative-hypnotics Neuroleptic Acetaminophen
Phencyclidine and Alcohols malignant syndrome Carbon tetrachloride
analogues Anticonvulsants Serotonin syndrome Cyanogenic glycosides
Withdrawal Barbiturates Strychnine Ethylene glycol
syndromes Benzodiazepines Membrane-active Methanol
Barbiturates GABA precursors agents Methemoglobin inducers
Benzodiazepines Muscle relaxants Amantadine Mushroom toxins
Ethanol Other agents Antiarrhythmics Organophosphate insecticides
Opioids GHB products Antihistamines Paraquat
Sedative-hypnotics Antipsychotics Metabolism disruptors
Sympatholytics Carbamazepine Antineoplastic agents
Cyclic Antiviral agents
antidepressants Colchicine
Stimulated Depressed Discordant Normal
Local anesthetics Hypoglycemic agents
Opioids (some) Immunosuppressive agents
Orphenadrine MAO inhibitors
Quinoline Metals
antimalarials Salicylate
Warfarin

o Stimulated
 Increased pulse, BP, RR< temperature, and neuromuscular activity
 can reflect sympathetic, antimuscarinic (anticholinergic), or
hallucinogen poisoning drug withdrawal
 Mydriasis (dilation of pupil) esp. in antimuscarinic poisoning (also
hot, dry, flushed skin, decreased bowel sound, and urinary
retention)
 diaphoresis, pallor, and increased bowel activity with varying
degrees of nausea, vomiting, abnormal distress, and occasionally
diarrhea
 Findings for specific drugs:
 reflex bradycardia (𝛼-adrenergic stimulants; e.g.
decongestants),
 hypotension (selective 𝛽-adrenergic stimulants; e.g. asthma
therapeutics)
 limb ischemia from ergot alkaloids
 rotatory nystagmus from phencyclidine and ketamine (the
only physiologic stimulants that cause this finding)
 delayed cardiac conduction from high doses of cocaine and
some anticholinergic agents (e.g. antihistamines, cyclic
antidepressants, and antipsychotics)
o Depressed
 Decreased pulse, blood pressure, RR, temperature, and
neuromuscular activity
 caused by “functional” sympatholytics, cholinergic (muscarinic and
nicotinic) agents, opioids, and sedative-hypnotic GABA-ergic agents
 Miosis (excessive constriction of the pupil)
 and other clues
o Discordant
 mixed vital sign and neuromuscular abnormalities
 
as observed in poisoning by asphyxiants, CNS syndromes,
membrane-active agents, and anion-gap metabolic acidosis (AGMA)
inducers
 manifestations of physiologic stimulation and depression occur
together or at different times during the clinical course
o Normal
 may be due to nontoxic exposure, psychogenic illness or poisoning
by “toxic time-bombs”; agent that are slowly absorbed, are slowly
distributed to their sites of action, require metabolic activation, or
disrupt metabolic processes

SUPPORTIVE CARE

• The goal of supportive therapy is to maintain physiologic homeostasis until detoxification is

accomplished and to prevent and treat secondary complications such as aspiration, bedsores, cerebral
and pulmonary edema, pneumonia, rhabdomyolysis, renal failure, sepsis, thromboembolic disease,
coagulopathy, and generalized organ dysfunction due to hypoxemia or shock.

• Admission to an intensive care unit is indicated for the following: patients with severe poisoning
(coma, respiratory depression, hypotension, cardiac conduction abnormalities, cardiac arrhythmias,
hypothermia or hyperthermia, seizures); those needing close monitoring, antidotes, or enhanced
elimination therapy; those showing progressive clinical deterioration; and those with significant
underlying medical problems. Patients with mild to moderate toxicity

To prevent

accidental poisoning, drugs and other potentially dangerous substances should be kept in their original
containers. Toxic substances, such as insecticides and cleaning agents, should not be put in drink bottles
or cups, even briefly. Other preventive measures include

Clearly labeling household products

Storing drugs (particularly opioids) and toxic substances in cabinets that are locked and out of the reach
of children

Using carbon monoxide detectors

Expired drugs should be disposed of by mixing them with cat litter or some other substance that is not
tempting and putting them in a trash container that is inaccessible to children. People can also call a
local pharmacy for advice on how to properly dispose of drugs. All labels should be read before taking or
giving any drugs or using household products.
TREATMENT Poisoning and Drug Overdose

GENERAL PRINCIPLES

• Treatment goals include support of vital signs, prevention of further poison absorption
(decontamination), enhancement of poison elimination, administration of specific antidotes, and
prevention of reexposure (Table 473e-3). Specific treatment depends on the identity of the poison, the
route and amount of exposure, the time of presentation relative to the time of exposure, and the
severity of poisoning. Knowledge of the offending agents’ pharmacokinetics and pharmacodynamics is
essential.

TABLE 473e-3Fundamentals of Poisoning Management

Supportive Care
Airway protection (ETT) Treatment of seizures (benzodiazepine, barbiturates-
GABA; pyridoxine; dopamine agonist, haloperidol; jangan
phenytoin!)
Oxygenation/ventilation Correction of temperature abnormalities
Treatment of arrhythmias Correction of metabolic derangements
Hemodynamic support Prevention of secondary complications
Prevention of Further Poison Absorption
Gastrointestinal decontamination Decontamination of other sites
Gastric lavage Eye decontamination
Activated charcoal Skin decontamination
Whole-bowel irrigation Body cavity evacuation
Dilution
Endoscopic/surgical removal, plus ipecac
Enhancement of Poison Elimination
Multiple-dose activated charcoal administration Extracorporeal removal
Alteration of urinary pH Hemodialysis
Chelation Hemoperfusion
Hemofiltration
Plasmapheresis
Exchange transfusion
Hyperbaric oxygenation
Administration of Antidotes
Neutralization by antibodies Metabolic antagonism
Neutralization by chemical binding Physiologic antagonism
Prevention of Reexposure
Adult education Notification of regulatory agencies
Child-proofing Psychiatric referral