poisons cyanide carbon monoxide arsenic and other metals organophosphates & nerve agents...

POISONS

• Cyanide

• Carbon monoxide

• Arsenic and other metals

• Organophosphates & Nerve Agents

• Inhalants (Toluene)

POISONSDefinitions

Therapeutic Index: The absolute difference between a tolerable (or therapeutic) concentration and a toxic concentrationPoisons: Substances with little or no therapeutic index;

we’ll use…‘Toxic’ Index

Poisons in our environment

•Plant Alkaloids, e.g. Strychnine•Venoms (Insect/Scorpion/Reptilian/Snake)•Mushrooms•amatoxin •Microbial (Botulinus toxin)•Chemical compounds (Cyanide CN)•Metals

Cyanide CNPoison in the environment-background levels

(sources/natural&industrial)

• Many natural sources of CN or CN

producing substances (cyanogenic)

• Peach pits, Cassava fruit, apple seeds

• Vitamin B12 (cyanocobalamin); many

metabolic processes produce CN of

cyanogenic chemicals; liver possesses

enzymatic pathways to detoxify CN

Cyanide CN Poison in the environment-background levels

• Salts NaCN & KCN used widely (electroplating, gold production and recovery)

• Many industrial uses• Rodenticides/Pesticides - fumigants• Nitroprusside used as an antihypertensive (action

through effect of NO on relaxing vascular muscle)• CN (HCN) produced by burning synthetic

materials

Cyanide CNMechanism of poison’s action

• Reversibly binds to a critical component of the respiratory chain (cytochrome c oxidase) causing a reversible stop in oxidative energy production

• Other enzyme systems are affected; oxidate energy production is the most important

Cyanide CNMechanism of poison’s action

• Without oxidative energy production, glucose and other sugar energy pathways are the only source of energy

• Two tissues in particular are obligate oxygen users: Brain and Heart

Cyanide CN Onset of action

• Toxic effects depend upon “route of administration” and concentration

• HCN gas when breathed is the fastest; death can occur within minutes; individuals can be incapacitated in HCN vapour within seconds

• Swallowed CN salts or cyanogenic substances take longer (absoprtion/ first pass effect)

Cyanide CNCourse of toxic effect

• CNS stimulation (counter effect) excitation

• headache and stiff neck

• giddiness

• change in breathing pattern (dyspnea); can be confused for hyperventilation

• nausea and vomiting


*** asphyxia without cyanosis***

• the oxygen remains in the blood and individuals color looks good

• convulsions and muscular contortion

• breathing: short inhalation-long exhalation

• heart races (tachycardia) then slows (bradycardia)


• Death due to asphyxia, cardiac and

respiratory arrest, with severe brain damage

(depending on time to death

Cyanide CN Disease states with similar (masking) symptoms

• Heart attack

• Acute asthma

Cyanide CN ‘Toxic’ Index

• Relatively small

• 50 mg HCN 200-300 mg of NaCN or KCN

Response PPM

• Immediately fatal 270

• Fatal in 10 min 181

• in 30 min 135

• 1 hr or dangerous to life 110-135

• slight symptoms (e.g. headache) 18-36

Cyanide CN

Routes of Absorption

• Primarily by breathing vapor or oral administration

• Dermal and Occular

Cyanide CN Pharmacokinetics – dynamics

• Bioavailability: up to 77% by inhalation/ 50% orally/ also dermal (slow) and occular absorption

• Vd 0.4 L/kg

• t ½ - approximately 1- 2 hr / converted to thiocyante by rhodanase enzyme


Blood concentrations mg/100 mL

• No symptoms 0.01-0.05

• Flushing/tachycardia 0.05-0.1

• Toxicity-death 0.1-0.25

• Coma-Death > 0.25


Overdose Treatment/Antidote

• Lilly antidote kit (sodium bicarbonate, amyl nitrate and sodium thiosulfate) with 100% oxygen

Carbon Monoxide COPoison in the environment-background levels (sources/natural;industrial)

• Primary source is incomplete combustion

Carbon Monoxide CO Mechanism of poison’s action

• Binds reversibly to hemoglobin - affinity of hemoglobin for CO > O2

Carbon Monoxide CO ‘Toxic’ Index

• Based on saturation of whole blood

• Endogenous < 1 %

• Up to 12% environmental (smokers living in high pollution areas) with no sequelae

• Toxicity 12-35%

• Fatal > 35% if acute/ >50% if gradual (i.e. accumulation over time.)

Carbon Monoxide CO Onset of action

• Depends strictly with saturation levels• e.g.

Response PPM

Headache (20%) 60 min @ 200

20 min @ 500

Death (50%) 80 min @ 500

20 min @ 1500

In an area of high concentration - minutes to incapacitation and death

Carbon Monoxide CO Course of toxic effect

• Headache, drowsiness, dizziness, NV, blurred vision, confusion, disorientation, dementia, bradycardia-tachycardia, hyperglycemia, seizures, coma, death

• Depends on concentration

Carbon Monoxide CO Disease states with similar (masking) symptoms

• Severe headache often not recognized as a symptom by victims

Carbon Monoxide CO Pharmacokinetics – dynamics

• Inhalation

• Half-life 5-6 hrs.

• Binds to hemoglobin carboxyhemoglobin

Carbon Monoxide CO Overdose Treatment/Antidote

• Oxygen and Hyberbaric pressure chamber

• Half-life 5-6 hrs in std atmosphere

• 30-90 minutes with 100% oxygen

• 30 minutes in hyperbaric chamber

METALS Poison in the environment-background levels (sources/natural;industrial)

• Most are relatively abundant in the environment or vital ligands for enzymes/co-enzymes and other macromolecules

• Metals vital to Health

Iron, Copper, Selenium, Zinc• Some Common Toxic Metals

Arsenic, Lead, Mercury, Thallium, Nickel, Cadmium, Iron

METALS Mechanism of poison’s action

• As- Multisystem disease due to inhibition of oxidative energy pathway attacks SH groups

• Pb - Same as As (SH groups)

• Tl - SH groups + subtitutes for K in ATPase (energy) pump.

METALS Mechanism of poison’s action

• Fe - Corrosive for GI tract -blood coagulation & cardiovascular collapse

• Hg - Binds to thiol and sulfhydryl groups

METALS ‘Toxic’ Index

Metal Background Toxic Fatal As 1 ng/mL > 0.5 mg/ 100 mL > 1 mg/100

mL Fe 65 - 175 mcg/ 100 mL > 350 mcg/ 100 mL > 1 gm Hg < 2 mcg/100 mL

Tolerable intake = 5 mcg/Kg

50 mcg/ 100 mL

Pb < 10 mcg/100 mL US intake 1980 - 82 = 50 mcg/day

> 50 mcg/ 100 mL

T l < 5 ng/ mL 12-15 mg/Kg or 0.05 mg/100 mL

METALS Onset of action

• As - 30 min - 2 hr; 200 mg Fatal 24 hr - 4 days

• Fe - 30 min - 6 hr; Fatal within 6 hrs or longer

• Hg - usually long, slow build up

• Pb - usually long, slow build up

• Tl - GI symptoms within 12-24 hrs.

METALS Course of toxic effect

Arsenic • Nausea &Vomiting, • bloody diarrhea, • abdominal pain, • burning on soles of feet, • sensory loss in extremities (lines in nail bed 4-6

weeks; Aldrich-Mees lines) • death due to circulatory collapse


Fe (Iron)• Primarily GI- affects lining; NV, GI pain,

cardiovascular collapse

Hg (Mercury)• CNS - tremor and loss of memory

Pb (Lead)• CNS - difficulty concentrating, lead (blue-black)

line on gums


Tl (Thallium)• Abdominal pain, • Nausea, Vomiting & Diarrhea, • peripheral neuropathy, • Aldrich-Mees lines, • *hair loss (2-4 weeks), • depressed respiration, delirium, seizure, coma, and

death

METALS Disease states with similar (masking) symptoms

• As -gastroenteritis, neurological disease

• Fe - gastroenteritis, but easily detected

• Hg - classic symptoms

• Pb - classic symptoms

• Tl - Viral disease; Guillain - Barre syndrome (often misdiagnosed)

METALS Routes of Absorption

• Mostly through industrial exposure or surreptitious consumption (poisoning) or suicide.

METALS Pharmacokinetics – dynamics

Metal Vd t1/2 Elimination* As 0.2 L/Kg 42-48 hrs renal detected in urine

for 30 hrs > 100 ng/mL Fe total body store 3-4 gm

hemosiderin in liver Depends on body burden

skin via desquamation; ~ 1 mg/day

Hg ? Elemental form poorly absorbed 40-70 days

Pb Iron, Zinc, Ca deficiencies increase absorption 50%; Widely distributed

blood = 28-36 days; bone = 20-30 years

Tl 1.5 L/Kg 2-4 days renal 24 hrs, then fecal *Most metals eliminated by the kidney

METALS Overdose Treatment/Antidote

Specific chemicals sequester metals

• As - Dimercaprol, Penicillamine, Succimer

• Fe -Deferoxamine, Polyethylene glycol

• Hg - Dimercaprol, Succimer

• Pb - Dimercaprol, Penicillamine, Succimer

• Tl - Prussian blue (exchanges K for Tl) not FDA

approved; acetylcysteine investigational

Organophosphates & Chemical Warfare Nerve Agents

Poison in the environment-background levels (sources/natural;industrial)

• Organophosphates were designed as pesticides against eukaryotic pests (e.g. they will also affect all pets and family members)

• Most warfare nerve agents attack the same metabolic pathways, but take minutes to kill rather than hours - days.

• Organochlorines (DDT; 2,4 D) are generally less toxic.

Parathion treated Cotton

Chemical Nerve Agents


Poison in the environment-background levels (sources/natural;industrial)

• Organophosphates: e.g. Parathion, (phosphorothionic acid O,O-diethyl O-(4-nitrophenyl) ester), Diazinon & Malathion

• Nerve agents: Sarin (isopropyl Methylphosphonofluoridate),

Soman, Tabun, VX (Methylphosphothionic acid S-(2-bis(1-

Methyl-Ethyl)Amino)Ethyl)O-Ethyl Ester)


Mechanism of poison’s action• Acetylcholinesterase inhibitors• Three stage action• Stage 1&2: Reversible for a period of time• Stage 3 : Becomes irreversible• Acetylcholinesterase has 2 binding sites for these

agents; the first can be reversed, the second can not.

• Nerve agents may slao penetrate the brain & disrupt GABA transmissions


‘Toxic’ Index

• Small to virtually non-existent

• Parathion

• Nerve agents: Sarin 4000x more potent than parathion

• Lethal inhaled doses of sarin, tabun & soman is 1mg

• VX - oily liquid absorbed dermally - 6 mg is lethal


‘Toxic’ Index• Maximum Control Limits (over 8 hrs)

Agent PPM

Sarin & Tabun 1 x 10-5 (0.00001)

VX 1 x 10-4 (0.0001)

CN 36

5 to 6 orders of magnitude (100,000 to 1 M) more potent than Cyanide.


Onset of action

• Organophosphates: depends on amount consumed hours to days to weeks & months

• Nerve agents: within 5 minutes

• Aging of nerve agent-acetylcholinesterase complex (stage 3):

Sarin 5 hours

Soman 2 minutes


Course of toxic effect

• Insomnia fatigue, memory loss, seizures, ataxia, coma, salivation, sweating, tearing, diarrhea, bradycardia, meiosis (pinpoint pupils) muscle twitching, weakness or paralysis.

• Death by respiratory arrest


Disease states with similar (masking) symptoms

Cholinergic symptoms:– salivation, – sweating, tearing,– diarrhea,– bradycardia, – meiosis (pinpoint pupils) – and memory loss/confusion

are classic symptoms for these agents


Routes of Absorption

• Readily absorpable by all routes

• Inhalation of gas and/or dust

• Dermal/Occular absorption (especially VX)

• Oral possible


Pharmacokinetics – dynamics

• Bioavailability not 100%

• hepatic conversion of organophosphates to weakly

active compounds

• onset of irreversible acetylcholinesterase binding

and extent of GABA inhibition

(pharmacodynamics) determine toxicity despite

kinetics


Pharmacokinetics – dynamics

• Organophosphates are cumulative

• Vd’s ?

• t 1/2 Malathion ~ 3hr others ?


Overdose Treatment/Antidote

• Anticholinergic - 1o Atropine

• Specific competative inhibitor of stage 2

binding is Pralidoxone (PAM)

• PAM binds phosphotase (or related) portion

of the toxin and reactivates the ACH ase

INHALANTSPoison in the environment-background levels (sources/natural;industrial)

• Toluene, Benzene, Gasolene• Chloroform, trichloroethylene• CFC’s• Anaesthethics• Other volatile substances

• Most are industrial/medicinal• Focus on Toluene

Toluene Mechanism of poison’s action

• Toluene - solvent (causes CNS depression and confusion) specific mechanism unknown

• Similarities to alcohols

• May alter lipid structure of membranes

• May effect receptor sites/membrane bound enzymes

• May affect cell proteins &/or RNA

Toluene ‘Toxic’ Index

• Tolerable limits are 50 PPM (188mg/m3 )

• Moderate

• Intoxicating - 0.1 to 0.25 mg/mL ...significant tolerance can develop!

• Fatal - 0.25 to 1.0 mg/mL

• Est. daily dose by inhalation 300 mcg

• Lethal oral dose 625 mg/kg

Toluene Forensic Caution

• Volatile solvent

• Sample concentrations can decrease over time

• Factors: – storage temperature– Type of cap/tube and tightness of seal– Amount of head space in tube/container

Toluene Onset of action

• Rapid as with all solvents/volatiles, especially when inhaled, effects begin within minutes

• “rapid in - rapid out”, but toluene is highly lipophillic, therefore: “rapid in - delayed out” and extended action

Toluene Course of toxic effect

• Marked intoxication, mental confusion, slurred speech, inability to concentrate, memory loss, hallucinations, coma, death

Toluene Disease states with similar (masking) symptoms

• Alcoholic

Toluene Routes of Absorption

• Absorption via all routes:

• Inhalation is fastest (30 minutes, e.g. glue

or paint thinner sniffing)

• Oral - up to 2 hrs.

• Dermal - time?

Toluene Pharmacokinetics – dynamics

• Vd: unkown but likely high…significantly retained in body

• Half life 48-72 hrs, but at least bi-phasic• Initial blood concentrations drop within

hours… then level out for days, especially in overdose (e.g. industrial accident) cases.

• Eliminated by kidneys, conversion to benzoic acid conjugated to form hippuric acid…excreted for days.

Toluene Overdose Treatment/Antidote

• Supportive therapy, oxygen if signifcant respiratory depression develops

• Many standard treatments e.g. epinephrine contra-indicated, due to combined cardiotoxicity or other toxicities

POISONS

The Bitter End!


• Metal Background• As - 1 ng/mL; Toxic > 0.5 mg/ 100 mL; Fatal > 1

mg/100 mL• Fe - 65 - 175 mcg/ 100 mL; Toxic > 350 mcg/ 100

mL• Hg - Background < 2 mcg/100 mL; Toxic > 50

mcg/ 100 mL; Tolerable intake = 5 mcg/Kg• Pb - Background < 10 mcg/100 mL; Toxic > 50

mcg/ 100 mL; US intake 1980-82 = 50 mcg/day• Tl - Background < 5 ng/ mL 12-15 mg/Kg toxic;

0.05 mg/100 mL in blood


Metal Background Toxic Fatal

As 1 ng/mL > 0.5 mg/100 mL

> 1 mg/100 mL

Fe 65 - 175 mcg/ 100 mL

> 350 mcg/ 100 mL > 1 gm

Hg < 2 mcg/100 mL Tolerable intake = 5 mcg/Kg

50 mcg/ 100 mL

Pb < 10 mcg/100 mL US intake ‘80 - 82 = 50 mcg/day

> 50 mcg/ 100 mL

Tl < 5 ng/ mL 12-15 mg/Kg or 0.05 mg/100 mL

METALS Pharmacokinetics – dynamics

• As - Vd = 0.2 L/Kg; t 1/2 = 42-48 hrs; Elimination - renal; detected in urine for 30 hrs > 100 ng/mL

• Fe - total body store 3-4 gm; hemosiderin in liver; Elimination - skin via desquamation; ~ 1 mg/day

• Hg - Elemental poorly absorbed; t 1/2 = 40-70 days; • Pb - Iron, Zinc, Ca deficiencies increase absorption 50%;

Widely distributed; t 1/2 blood = 28-36 days; bone = 20-30 years

• Tl - Vd = 1.5 L/Kg; t 1/2 = 2-4 days; Elimination - renal 24 hrs, then fecal

*Most metals eliminated by the kidney

poisons cyanide carbon monoxide arsenic and other metals organophosphates & nerve agents...

Documents

cn slide

cyanide cn poison

cyanide cn toxic index

cn salts

cyanide cn disease states

heart slide

death slide

occular slide