1 Toxicological -Agents By: Prof. Helen C. Santos JFSM-UPHSD
Transcript
1. 11 Toxicological -Agents By: Prof. Helen C. Santos
JFSM-UPHSD
2. 22 Common Toxicological Agents: - Drugs - Toxic household
products - Environmental and occupational solvents Heavy metals Air
pollutants Solvents Insecticides Microorganisms
3. 33 Drugs; Acetaminophen - commonly involve in: suicide
attempts as sole agent or in accidental poisoning combination with
other drugs - ingestion of > 150 200 mg/kg => children
>7=g total => adults i.e. highly toxic metabolite=>
produced in the liver S x S: initially=> asymptomatic or GIT
upset => nausea and vomiting after 24-36hrs. s x s=> evidence
of liver injury appears, i.e
4. 44 5 Major Air Pollutants: - CO = 52% NO = 14% - SO = 14% -
Hydrocarbons = 14% - Particulate matter = 4% Sources: -
Transportation - space heating - Industry - refuse disposal -
Generation of electric power
5. 55 CARBON MONOXIDE: > Colorless, tasteless, odorless, and
non- irritating gas > by-product of incomplete combustion >
ave. conc. in atmosphere = 0.1 ppm heavy traffic >100.0 ppm >
TLV-TWA = 25.0 ppm TLV-TWA = conc. for a normal 8hr.workday or 40
workweek to w/c workers may be repeatedly exposed w/o adverse
effects
6. 66 Mechanism of action how CO exert its toxic effect: CO +
Hb COHb CO has 220x affinity to Hb compare to O2 therefore: * O2
cannot be transported to the whole part of the body * COHb
interferes w/ the dissociation of O2 from the remaining OHb
reducing the the transfer of O2 to tissues * CO has also a direct
damaging effect on the body cells - Brain and heart are the most
sensitive organs on CO effects
7. 77 - Normal nonsmoking adults COHb level endogenous
formation of CO from heme catabolism - Smokers = 5-10% saturation
(depending on their smoking habits) - Individual breathing 0.1% CO
(1000ppm) COHb level of about 50%
8. 88 Clinical Effects of CO Exposure: * Principal S x S: -
Hypoxia w/c progress into: > psychomotor impairment >
headache and tightness in the temporal area > confusion and loss
of visual acuity > tachycardia, tachypnia, syncope > deep
coma, convulsions, shock and respiratory failure
9. 99 * Other s x s of CO poisoning: - Delayed neuropsychiatric
impairment - Slow resolution of behavioral consequences
10. 1010 * Variability of individual responses to different
COHb levels: - 60% - death may ensue * Aggravating Factors for CO
Clinical Effects: - Heavy labor - High altitudes - High ambient
temperature
11. 1111 - presence of cardiovascular diseases increase risk w/
CO exposure - pregnancy-fetus=>susceptible to CO effects -
smoking CO poisoning= chronic among cigarette smokers e.g. of
effect: atherosclerotic coronary disease
12. 1212 Treatment of Carbon Monoxide Poisoning: * Acute
intoxication- > Removal of the individual from the exposure
source > Maintenance of respiration i.e. aim. Of O2specific
antagonist to CO Elimination of Halftime of CO: -- room air at 1
atm. =320 mins. -- w/ 100% O2 = 80 mins. -- w/ hyperbaric O2 at 2-3
atm.=20mins.
13. 1313 SULFUR DIOXIDE - Colorless - Irritant gas - TLV-TWA =
2ppm; TLV-STEL= 5 ppm * TLV-STEL = Threshold Limit Value-Short Term
Exposure Limit = max. conc. that should not be exceeded at anytime
during a 15 min. exposure period - Commonly Affected: > elderly
> w/ preexisting cardiac or respiratory disease
14. 1414 Mechanism of Action How SO2 Exerts its Effect: - On
contact with moist membranes, SO2 forms sulfurous acid w/c is
responsible for its severe irritant effects on the eyes, mucous
membranes and skin Absorption of SO2: - Absorbed thru the upper
respiratory tract - 90% of the inhaled is absorbed
15. 1515 Clinical Effects of SO2 Poisoning: * irritation of the
eyes, nose and throat * reflex bronchoconstriction * delayed onset
of pulmonary edema severe exposure * chronic exposure= associated
w/ aggravation of chronic cardiopulmonary disease
16. 1616 Treatment for SO2 Poisoning: - no specific treatment -
depends on therapeutic maneuvers used in respiratory tract
irritation
17. 1717 NITROGEN OXIDES * NO2 brownish irritant gas associated
w/ fires - formed from fresh silage - common exposures of farmers -
can lead to silo-fillers disease - TLV-TWA = 3ppm; TLV-STEL =5ppm
-> Mech. Of Action: NO2 is a deep lung irritant producing
pulmonary edema
18. 1818 Effects on Exposure to NO2: > 25ppm irritating to
some individuals > 50ppm moderately irritating to the eyes and
nose > 1hr to 50ppm pulmonary edema and perhaps subacute or
chronic pulmonary lesions > 100ppm pulmonary edema to death >
On acute exposure type I cells are affected
19. 1919 Clinical Effects of NO2 Exposure: Acute - Irritation
of eyes and nose - Cough - Mucoid or frothy sputum - Dyspnea and
chest pain - Pulmonary edema w/in 1-2hrs. - s x s may subside in
about 2 wks.
20. 2020 -- Drug Therapy for NO2 Intoxication: Bronchodilators
Sedatives Antibiotics
21. 2121 OZONE O3 bluish irritant gas - normally occurs in the
atmosphere - it is an important absorbent of UV light - source in a
workplace: * High-voltage electrical equipment * Ozone-producing
devices use for air and water purification * urban-polluted air *
TLV-TWA = 0.05; TLV-STEL = NA
22. 2222 Clinical Effects of Ozone: * Mild exposure=upper
respiratory tract irritation * Severe exposure = deep lung
irritation w/ pulmonary edema * S X S : - formation of reactive
free radicals - gas causes: shallow rapid breathing : decrease in
pulmonary compliance - enhanced sensitivity of the lungs to
bronchoconstrictors
23. 2323 - exposure to 0.1ppm for 10-30 mins.=> irritation
and dryness of the throat - >0.1ppm. = changes in visual acuity
- substernal pain - dyspnea - >0.8ppm= pulmonary function is
impaired - human = airway hyper responsiveness = airway
inflammation
24. 2424 Clinical Treatment of Ozone Toxicity: - no specific
treatment for acute O3 intoxication - Management depends on
therapeutic measures utilized for: * deep lung irritation *
noncardiogenic pulmonary edema
25. 2525 HEAVY METALS
26. 2626 LeadLead Possible sources of exposuresPossible sources
of exposures:: > Commercial application of lead-> Commercial
application of lead- - production and storage of batteries-
production and storage of batteries - metal alloys- metal alloys -
solder- solder - glass- glass - ceramics- ceramics > Exposure to
air, water, and food due> Exposure to air, water, and food due
to contamination of gasolineto contamination of gasoline >
Workplace> Workplace
27. 2727 Concern over the effects of low-level leadConcern over
the effects of low-level lead exposure:exposure: >
neurocognitive function> neurocognitive function > blood
pressure at blood lead concentration> blood pressure at blood
lead concentration once considered normal or safeonce considered
normal or safe -> lead serves no useful purpose in the-> lead
serves no useful purpose in the human bodyhuman body -> in key
target organs e.g. the developing-> in key target organs e.g.
the developing CNSCNS no safe threshold of leadno safe threshold of
lead exposureexposure
28. 2828 PharmacokineticsPharmacokinetics of Leadof Lead
AbsorptionAbsorption Factors that affect absorption:Factors that
affect absorption: Form of leadForm of lead Inorganic lead absorbed
through the :Inorganic lead absorbed through the : respiratory
tractrespiratory tract GITGIT skin = absorbed poorlyskin = absorbed
poorly Organic lead well absorbed through the skinOrganic lead well
absorbed through the skin - lead dust =>absorbed through the
respiratory tract- lead dust =>absorbed through the respiratory
tract => most common cause of industrial=> most common cause
of industrial poisoningpoisoning - leaded antiknock gasoline =>
well absorbed- leaded antiknock gasoline => well absorbed
through the skinthrough the skin
29. 2929 AbsorptionAbsorption Route of entryRoute of entry
-> intestinal tract - 1-> intestinal tract - 1oo route of
entry inroute of entry in nonindustrial lead exposurenonindustrial
lead exposure -> GIT - absorption depends upon the nature->
GIT - absorption depends upon the nature of lead compoundof lead
compound - generally: adults absorb = 10-15%- generally: adults
absorb = 10-15% of the ingested amountof the ingested amount young
= up to 50% of ingestedyoung = up to 50% of ingested low dietary
calcium associated withlow dietary calcium associated with iron
deficiency increased leadiron deficiency increased lead ingestion
on an empty stomach absorptioningestion on an empty stomach
absorption
30. 3030 Distribution of LeadDistribution of Lead Absorbed
lead- from respiratory tract and GITAbsorbed lead- from respiratory
tract and GIT bind to erythrocytesbind to erythrocytes bone brain
kidney liver muscle gonadsbone brain kidney liver muscle gonads
marrowmarrow subperiosteal surface of bonesubperiosteal surface of
bone bone matrixbone matrix - crosses the placenta- crosses the
placenta poses a potentialposes a potential hhazard to the
fetusazard to the fetus
31. 3131 Elimination of LeadElimination of Lead Lead clearance
= multicompartment modelLead clearance = multicompartment model
composed of:composed of: -> blood-> blood -> soft tissues
half-life = 1-2 mos.-> soft tissues half-life = 1-2 mos. ->
skeleton half-life = years-decades-> skeleton half-life =
years-decades Eliminated lead ~70%Eliminated lead ~70% urineurine -
lesser amount excreted through:- lesser amount excreted through: *
bile * nails* bile * nails * skin * sweat* skin * sweat * hair *
breast milk* hair * breast milk
32. 3232 Elimination of leadElimination of lead - fraction not
undergoing prompt excretion- fraction not undergoing prompt
excretion ~ half of the absorbed lead~ half of the absorbed lead
incorporatedincorporated into the skeletoninto the skeleton
repository of morerepository of more than 90% of the body lead
burden inthan 90% of the body lead burden in most adultsmost adults
* patients = high body lead burdens:* patients = high body lead
burdens: -> slow release from the skeleton-> slow release
from the skeleton elevate blood lead concentrationselevate blood
lead concentrations for yrs. => after exposure ceasesfor yrs.
=> after exposure ceases
33. 3333 Elimination of leadElimination of lead ->
pathologic high bone turnover states-> pathologic high bone
turnover states e.g. hyperthyroidisme.g. hyperthyroidism or
prolonged immobilizationor prolonged immobilization frank leadfrank
lead intoxicationintoxication * quantitation of lead burden in
bone* quantitation of lead burden in bone -> noninvasive x-ray
fluorescence = best-> noninvasive x-ray fluorescence = best
measure of long-term cumulative leadmeasure of long-term cumulative
lead absorptionabsorption
34. 3434 Toxicology of LeadToxicology of Lead Form entering the
bodyForm entering the body -> inorganic = lead oxides->
inorganic = lead oxides lead saltslead salts -> organic =
tetraethyl lead-> organic = tetraethyl lead Major route of
absorptionMajor route of absorption -> inorganic = GIT->
inorganic = GIT respiratoryrespiratory -> organic = skin->
organic = skin GITGIT respiratoryrespiratory
35. 3535 DistributionDistribution -> inorganic = soft
tissues-> inorganic = soft tissues skeleton i.e.skeleton i.e.
>90% of adult body burden>90% of adult body burden ->
organic = soft tissues especially: liver-> organic = soft
tissues especially: liver : CNS: CNS * Major clinical effects of
lead intoxication:* Major clinical effects of lead intoxication:
-> inorganic-> inorganic CNS deficits hypertensionCNS
deficits hypertension peripheral neuropathy reproductiveperipheral
neuropathy reproductive anemia toxicityanemia toxicity
nephropathynephropathy
36. 3636 * Major clinical effects* Major clinical effects ->
organic = encephalopathy-> organic = encephalopathy * Mechanism
of action* Mechanism of action -> inorganic = inhibits
enzymes-> inorganic = inhibits enzymes = interferes w/ essential
cations= interferes w/ essential cations such as: calcium, iron
& zincsuch as: calcium, iron & zinc = disturbs cellular
redox status= disturbs cellular redox status = alters membrane
structures &receptors= alters membrane structures
&receptors -> organic = hepatic dealkylation (fast)->
organic = hepatic dealkylation (fast)
trialkymetabolitestrialkymetabolites (slow)(slow) dissociation to
leaddissociation to lead
37. 3737 * Metabolism and elimination* Metabolism and
elimination -> inorganic = renal => major-> inorganic =
renal => major = feces minor= feces minor breast milkbreast milk
-> organic = urine major-> organic = urine major fecesfeces =
sweat => minor= sweat => minor
38. 3838 Effect of lead on the different body organ
systemEffect of lead on the different body organ system Nervous
systemNervous system -> most sensitive target organ for leads
toxic-> most sensitive target organ for leads toxic effect =
developing nervous system:effect = developing nervous system: *
fetus* fetus * young child* young child -> young children->
young children - blood lead concentrations adults - less sensitive
to CNS lead effects- less sensitive to CNS lead effects - blood
lead concentration >30mcg/dl- blood lead concentration
>30mcg/dl * behavioral* behavioral * neurocognitive effects*
neurocognitive effects sign & symptoms:sign & symptoms: ..
irritability .. fatigue.. irritability .. fatigue .. sleep
disturbance .. anorexia.. sleep disturbance .. anorexia ..
decreased libido.. decreased libido .. impaired visual-motor
coordination.. impaired visual-motor coordination .. slowed
reaction time.. slowed reaction time
40. 4040 Effects of lead on body organ system- CNSEffects of
lead on body organ system- CNS other frequent complaints:other
frequent complaints: .. headache .. myalgias.. headache .. myalgias
.. arthralgias.. arthralgias tremors = less commontremors = less
common - blood lead concentrations >100mcg/dl- blood lead
concentrations >100mcg/dl lead encephalopathylead encephalopathy
increased intracraneal pressureincreased intracraneal pressure
=> ataxia => convulsions=> ataxia => convulsions =>
stupor => death=> stupor => death => coma=>
coma
41. 4141 Effect of lead on body organ system - CNSEffect of
lead on body organ system - CNS - accentuate an age-related decline
in cognitive- accentuate an age-related decline in cognitive
function in older adultsfunction in older adults - chronic
high-dose exposure = following- chronic high-dose exposure =
following mos.-yrs. of blood lead concs. >100mcg/dlmos.-yrs. of
blood lead concs. >100mcg/dl peripheral neuropathy =>
clinicallyperipheral neuropathy => clinically .. painless
weakness of the extensors.. painless weakness of the extensors
particularly in the upper extremityparticularly in the upper
extremity --> wrist-drop--> wrist-drop .. detectable by
electrodiagnostic testing.. detectable by electrodiagnostic
testing
42. 4242 Lead effects on body organ systemLead effects on body
organ system Blood - anemiaBlood - anemia -> lead interferes w/
heme synthesis by:-> lead interferes w/ heme synthesis by: *
blocking the incorporation of iron into* blocking the incorporation
of iron into protoporphyrin IXprotoporphyrin IX * inhibiting the
function of enzymes in the* inhibiting the function of enzymes in
the heme synthesis pathway includingheme synthesis pathway
including .. aminolevulinic acid dehydratase.. aminolevulinic acid
dehydratase .. ferrochelatase.. ferrochelatase elevation of blood
lead concentrationelevation of blood lead concentration => 2 8
wks.=> 2 8 wks. >> 30 50mcg/dl30 50mcg/dl
43. 4343 Lead effect on body organ system - BloodLead effect on
body organ system - Blood increased of heme precursors
detectableincreased of heme precursors detectable in the whole
blood:in the whole blood: .. free erythrocyte protoporphyrin.. free
erythrocyte protoporphyrin .. zinc chelate zinc protoporphyrin..
zinc chelate zinc protoporphyrin -> increases erythrocyte
fragility-> increases erythrocyte fragility decreaseddecreased
red cell survival time => anemiared cell survival time =>
anemia - frank hemolysis- frank hemolysis -> occur w/ high
exposure-> occur w/ high exposure -> presence of basophilic
stippling on-> presence of basophilic stippling on peripheral
blood smear = consequenceperipheral blood smear = consequence
44. 4444 of lead inhibition of the enzyme 35-of lead inhibition
of the enzyme 35- pyrimidine nucleotidasepyrimidine nucleotidase
diagnostic cluediagnostic clue for lead intoxicationfor lead
intoxication KidneyKidney - renal interstitial fibrosis- renal
interstitial fibrosis - nephrosclerosis- nephrosclerosis chronic
high-dose of lead exposure =>chronic high-dose of lead exposure
=> mos. yrs. of blood lead conc.mos. yrs. of blood lead conc.
>> 80mcg/dl80mcg/dl - lead nephropathy- lead nephropathy
latency period of yrs.latency period of yrs.
45. 4545 - altered uric acid excretion by the kidney- altered
uric acid excretion by the kidney recurrent bouts of gouty
arthritisrecurrent bouts of gouty arthritis =>saturnine
gout=>saturnine gout - transient azotemia- transient azotemia
acute high-dose leadacute high-dose lead exposureexposure
intrarenal vasoconstrictionintrarenal vasoconstriction Reproductive
organsReproductive organs - high-dose lead exposure = recognized
risk- high-dose lead exposure = recognized risk factor for:factor
for: * stillbirth* stillbirth * spontaneous abortion* spontaneous
abortion
46. 4646 - impact of low-level lead exposure on the- impact of
low-level lead exposure on the reproductive organ:reproductive
organ: -> female-> female * low birth weight* low birth
weight * preterm delivery* preterm delivery * spontaneous abortion
detected odds ratio* spontaneous abortion detected odds ratio = 1.8
: 5mcg/dl increase in maternal= 1.8 : 5mcg/dl increase in maternal
blood lead across ~ range 5-20mcg/dlblood lead across ~ range
5-20mcg/dl -> male- blood lead conc. > 40mcg/dl-> male-
blood lead conc. > 40mcg/dl diminished or aberrant
spermdiminished or aberrant sperm productionproduction
47. 4747 Effect of lead on body organ systemEffect of lead on
body organ system GITGIT - moderate lead poisoning- moderate lead
poisoning * loss of appetite* loss of appetite * constipation*
constipation * diarrhea less commonly* diarrhea less commonly -
high dosage- high dosage intermittent bouts of severeintermittent
bouts of severe colicky abdominal pain => lead coliccolicky
abdominal pain => lead colic spasmodic contraction of the
smoothspasmodic contraction of the smooth muscle of the intestinal
wallmuscle of the intestinal wall
48. 4848 -- heavily exposed individuals to lead w/ poorheavily
exposed individuals to lead w/ poor dental hygienedental hygiene
circulating lead + sulfur (released by microbes)circulating lead +
sulfur (released by microbes) dark deposits of PbSdark deposits of
PbS gingival lead lines i.e. at the gingivalgingival lead lines
i.e. at the gingival marginmargin Cardiovascular
systemCardiovascular system - relatively low-level of lead exposure
by the- relatively low-level of lead exposure by the general
publicgeneral public independent risk factorindependent risk factor
for HPNfor HPN - lead increases BP in animals- lead increases BP in
animals interaction w/interaction w/ calcium mediated contraction
of vascular smoothcalcium mediated contraction of vascular smooth
musclemuscle
49. 4949 Major forms of lead intoxicationMajor forms of lead
intoxication Inorganic lead poisoningInorganic lead poisoning ->
acute industrial inhalation of large-> acute industrial
inhalation of large quantities of lead oxide fumesquantities of
lead oxide fumes - ingestion by small children of- ingestion by
small children of large dose of lead in:large dose of lead in: ..
lead based paints.. lead based paints .. contaminated food or
drink.. contaminated food or drink - S x S: severe- S x S: severe
occur afteroccur after several days or weeks ofseveral days or
weeks of recurrent exposurerecurrent exposure
50. 5050 Forms of lead intoxicationForms of lead intoxication -
S x S of acute inorganic intoxication:- S x S of acute inorganic
intoxication: * encephalopathy* encephalopathy * colic* colic *
hemolytic anemia or anemia w/* hemolytic anemia or anemia w/
basophilic stippling if exposure isbasophilic stippling if exposure
is subacutesubacute * elevated aminotransferases* elevated
aminotransferases - dx = difficult- dx = difficult = mistaken for:
appendicitis, peptic ulcer,= mistaken for: appendicitis, peptic
ulcer, pancreatitis or infectious meningitispancreatitis or
infectious meningitis
51. 5151 = subacute cases S x S:= subacute cases S x S: *
headache* headache * fatigue* fatigue * intermittent abdominal
cramps* intermittent abdominal cramps * myalgias* myalgias *
arthralgias* arthralgias mistaken for a flu-like viral
illnessmistaken for a flu-like viral illness maymay not come to
medical attentionnot come to medical attention = radiopacities=
radiopacities visible on abdominalvisible on abdominal radiographs
upon ingestion of: paintradiographs upon ingestion of: paint chips,
glazes or weightschips, glazes or weights
52. 5252 Forms of lead intoxicationForms of lead intoxication
-> chronic inorganic lead poisoning-> chronic inorganic lead
poisoning - multisystemic findings:- multisystemic findings: *
constitutional complaints* constitutional complaints .. anorexia..
anorexia .. fatigue.. fatigue .. malaise.. malaise * neurologic
complaints* neurologic complaints .. headache.. headache ..
difficulty in concentrating.. difficulty in concentrating ..
irritability.. irritability .. depressed mood.. depressed mood
54. 5454 => chronic lead intoxication = considered in=>
chronic lead intoxication = considered in child w/:child w/: *
neurocognitive deficits* neurocognitive deficits * growth
retardation* growth retardation * developmental delay*
developmental delay dx = best confirmed by lead concentrationdx =
best confirmed by lead concentration determination from whole
blooddetermination from whole blood .. test reflects lead currently
circulating.. test reflects lead currently circulating in blood and
soft tissuesin blood and soft tissues .. not a reliable marker of
either recent.. not a reliable marker of either recent or
cumulative lead exposureor cumulative lead exposure
55. 5555 = concentration of lead in bone= concentration of lead
in bone noninvasivenoninvasive K x-ray fluorescence measurement of
leadK x-ray fluorescence measurement of lead in bone:in bone: *
correlated w/ long-term cumulative lead* correlated w/ long-term
cumulative lead exposureexposure * its relationship to numerous
lead-related* its relationship to numerous lead-related
disordersdisorders = measurement of lead excretion in the urine=
measurement of lead excretion in the urine following a single dose
of a chelating agentfollowing a single dose of a chelating agent
=> chelation challenge test=> chelation challenge test 1100
reflects the lead content of soft tissuesreflects the lead content
of soft tissues
56. 5656 * may not be a reliable marker of:* may not be a
reliable marker of: .. long-term lead exposure.. long-term lead
exposure .. remote past exposure.. remote past exposure .. skeletal
lead burden.. skeletal lead burden
57. 5757 Forms of lead poisoningForms of lead poisoning
Organolead poisoning now very rareOrganolead poisoning now very
rare tetraethyl and tetramethyl lead = phased-outtetraethyl and
tetramethyl lead = phased-out - lead stearate or lead naphthenate-
lead stearate or lead naphthenatestill usedstill used - organolead
= well absorbed through:- organolead = well absorbed through: *
respiratory tract* respiratory tract * skin* skin
volatilityvolatility lipid solubilitylipid solubility
58. 5858 - organolead = main target => CNS- organolead =
main target => CNS produces dose-dependent effects such
as:produces dose-dependent effects such as: * neurocognitive
deficits* neurocognitive deficits * insomnia* insomnia * delirium*
delirium * hallucination* hallucination * tremor* tremor *
convulsion* convulsion * death* death
59. 5959 Treatment for lead poisoningTreatment for lead
poisoning Inorganic lead poisoningInorganic lead poisoning -
termination of exposure- termination of exposure - supportive care-
supportive care - judicious use of chelation therapy- judicious use
of chelation therapy -> lead encephalopathy-> lead
encephalopathy medicalmedical emergency=>intensive supportive
careemergency=>intensive supportive care some clinicians
advocate:some clinicians advocate: * initiated w/ I.M.dimercaprol*
initiated w/ I.M.dimercaprol * followed in 4 hrs.=> by
concurrent* followed in 4 hrs.=> by concurrent adm. of
dimercaprol and EDTAadm. of dimercaprol and EDTA
60. 6060 Treatment for lead poisoning - inorganicTreatment for
lead poisoning - inorganic * parenteral chelation=> limited*
parenteral chelation=> limited institutedoral chelator succimer
=> instituted -> cerebral edema-> cerebral edema
corticosteroids andcorticosteroids and mannitolmannitol ->
seizures-> seizures anticonvulsantanticonvulsant ->
radiopacities on abdominal radiographs-> radiopacities on
abdominal radiographs presence of retained lead objectspresence of
retained lead objects GITGIT decontaminationdecontamination
adequate urine flow=> maintainedadequate urine flow=>
maintained overhydration => avoidedoverhydration =>
avoided
61. 6161 Treatment of lead poisoning - inorganicTreatment of
lead poisoning - inorganic edetate calcium
disodium(CaNa2EDTA)edetate calcium disodium(CaNa2EDTA) => I.V.
administered; 1000 1500mg/m=> I.V. administered; 1000 1500mg/m22
/d/d ~ 30-50mg/kg/d by continuous~ 30-50mg/kg/d by continuous
infusion for 5daysinfusion for 5days -> symptomatic lead
intoxication w/o-> symptomatic lead intoxication w/o
encephalopathyencephalopathy initiated w/ succimerinitiated w/
succimer end point of chelation:end point of chelation: =
resolution of symptoms= resolution of symptoms = return of lead
concentration to pre-= return of lead concentration to pre- morbid
rangemorbid range
62. 6262 Treatment of lead poisoning-inorganicTreatment of lead
poisoning-inorganic -> patients w/ chronic exposure->
patients w/ chronic exposure cessationcessation of chelationof
chelation upward rebound in bloodupward rebound in blood lead
concentration => lead reequilibrateslead concentration =>
lead reequilibrates from bone lead storesfrom bone lead stores
-> for all children w/ blood lead concentration-> for all
children w/ blood lead concentration >> 45mcg/dl45mcg/dl
chelation is recommendedchelation is recommended -> clinical
trial of succimer in children w/-> clinical trial of succimer in
children w/ blood lead conc. between 25 & 44mcg/dlblood lead
conc. between 25 & 44mcg/dl no benefit on neurocognitive fxn
orno benefit on neurocognitive fxn or long-term blood lead
reductionlong-term blood lead reduction
63. 6363 Treatment of lead poisoning Inorganic ->
prophylactic use of chelating agents in the workplace = never a
substitute for: * reduction of excessive * prevention exposure
Organic -> initial treatment = decontaminating the skin =
prevent further exposure -> seizures = appropriate
anticonvulsants -> high blood lead conc. present =
chelation
64. 6464 Arsenic - naturally occurring earth element ->
ground water = contains high arsenic level leached from natural
mineral deposits - use as: * constituent of commercial and
industrial products .. use in the manufacture of semiconductors
-> arsine gas = manufactured for use in semiconductor
industry
65. 6565 = generated accidentally when arsenic-containing ores
come in contact w/ acidic solutions w/ potent hemolytic effect ..
wood preservatives for industrial applications e.g. marine timbers,
utility poles .. nonferrous alloys .. glass .. gel-based
insecticidal ant baits .. veterinary pharmaceuticals
66. 6666 * component pharmaceuticals for man ..Fowlers solution
contains 1% potassium arsenite = widely use medicine in 18th- 20th
century .. Organic arsenicals = 1st pharmaceutical antibiotics
replaced by penicillin and other effective and less toxic agents ..
Lewisite (dichloro [2-chlorovinyl]arsine) = organoarsenicals
developed as chemical warfare agents
67. 6767 .. Arsenic trioxide = reintroduced in US pharmacopoeia
in 2000 orphan drug for the tx of: --> relapsed acute
promyelocytic leukemia --> use in experimental cancer tx
protocols .. Melarsoprol = trivalent arsenical tx advance African
trypanosomiasis * agent of deliberate poisoning
68. 6868 Pharmacokinetics of arsenic - soluble arsenic
compounds = well absorbed * respiratory * GIT * percutaneous
limited clinically significant after heavy exposure to concentrated
arsenic reagents arsonic acid and dimethylarsenic acid excreted
along with the residual arsenic in the urine
69. 6969 Pharmacokinetics of arsenic - chronic daily absorption
: < 1000mcg of soluble inorganic arsenic ~ 2/3 of absorbed dose
=> urine - after massive ingestion elimination half-life =>
prolonged - inhalation of arsenic compounds of low solubility
prolonged retention in the lung may not be reflected by urinary
arsenic excretion
70. 7070 keratinized tissues after exposure nails skin contain
elevated level of arsenic (indistinguishable from that absorbed
internally) urine level = normal
71. 7171 Pharmacodynamics of arsenic - inorganic trivalent
arsenic = As3+ ; arsenite 2-10x more acutely toxic than inorganic
pentavalent arsenic = As5+ ; arsenate - recent studies trivalent
form of methylated metabolite e.g. monomethylarsonous acid (MMAIII
)>toxic than the inorganic parent cpd. - action how arsenic
exerts its toxic effect : interference with enzymatic function
=> As3+ + sulfhydryl group or substitution for PO4 3-
72. 7272 inorganic arsenic or its metabolites may -> induce
oxidative stress -> alter gene expression -> interfere w/
cell signal transduction arsine gas oxidized in vivo exerts a
potent hemolytic effect = associated w/ alteration of ion flux
across the erythrocyte membrane = disruption of cellular
respiration in other tissues
73. 7373 Pharmacodynamics of arsenic - arsenic => recognized
human carcinogen => associated w/ cancer: .. lung .. bladder ..
skin - marine organisms=>contain large amounts of ..
trimethylated organoarsenic .. arsenobetain- no known toxic effect
in mammals excreted in urine unchanged .. variety of arsenosugars
partially metabolized to dimethylarsenic acid
74. 7474 Major forms of arsenic intoxication Acute inorganic
arsenic poisoning -> exposure to high doses = tens -100 of mgs.
of soluble inorganic compounds GIT S x S w/c include: .. nausea ..
diarrhea .. vomiting .. abdominal pain diffuse capillary leak + GIT
fluid loss hypotension - shock - death
75. 7575 cardiopulmonary toxicity => includes: .. congestive
cardiomyopathy .. cardiogenic & noncardiogenic pulmonary edema
.. ventricular arrhythmias occur promptly or after a delay of
several days pancytopenia usually develops w/in a wk. basophilic
stippling of erythrocytes may be present soon after
76. 7676 CNS effects: * delirium occur w/in first *
encephalopathy few days of * coma intoxication * ascending
sensorimotor peripheral neuropathy develop after a delay of 2-6wks.
- ultimately involve the proximal musculature ---> neuromuscular
respiratory failure
77. 7777 * transverse white striae = Aldrich-Mees lines visible
in the nails, months after an episode of acute poisoning -> Dx
and tx of acute inorganic arsenic poisoning: - Dx : individuals
presenting initially => abrupt onset of gastroenteritis +
hypotension + metabolic acidosis * followed by=> cardiac
dysfunction, pancytopenia and peripheral neuropathy
78. 7878 * confirmation of dx determination of inorganic
arsenic level and its metabolites in the urine range = several
thousand in the first 2-3 days following acute symptomatic
poisoning blood not used for dx purposes => arsenic disappears
rapidly from the blood except in anuric patients
79. 7979 - tx based on: * appropriate gut decontamination *
intensive supportive care * prompt chelation w/: .. unithiol 3-5
mg/kg I.V. every 4-6hrs. .. or dimercaprol, 3-5 mg/kg, I.M. every
4-6 hrs in animal studies: * efficacy of chelation = highest if
administered w/in minutes hours after arsenic exposure
80. 8080 succimer effective in animal models - has a higher
therapeutic index than dimercaprol - available only for oral
administration => use = not advisable in the initial tx of acute
arsenic poisoning = severe gastroenteritis and splanchnic edema may
limit absorption by oral route
81. 8181 Chronic inorganic arsenic poisoning -> appearance
of symptoms vary with: * dose * interindividual tolerance - chronic
absorption > 500-1000mcg/d evidence of overt noncarcinogenic
effects such as: .. constitutional symptoms of: * fatigue *
weakness * weight loss
82. 8282 .. anemia .. nonspecific gastrointestinal complaints
.. sensorimotor peripheral neuropathy stocking glove pattern of
dysesthesia skin changes most characteristic effects develop after
years of exposure w/c include: * raindrop pattern of
hyperpigmentation * hyperkeratoses involving the palms
83. 8383 .. peripheral vascular disease and noncirrhotic portal
hypertension possible link to: * hypertension * diabetes * chronic
nonmalignant respiratory disease - years after exposure to not high
enough doses to elicit acute or chronic effects cancer of: * lungs
* bladder * skin * other sites
84. 8484 - in cancer chemotherapy : arsenite dose = 10-20mg/day
for wks-few months associated w/ prolongation of the QT interval on
the ECG occasionally resulted in malignant ventricular arrhythmias
such as torsade de pointes -> dx of chronic arsenic poisoning: -
integration of clinical findings w/ confirmation of exposure -
urinary levels of total arsenic < 30 mcg/L
85. 8585 - or 50 mcg/24 hr. in general population return to
normal w/in days-wks after exposure ceases seafood should be
avoided 3days prior to submission of urine sample .. contains large
amount of nontoxic organoarsenic - arsenic content of hair and
nails intoxication dominated by profound hemolytic effects - after
a latent period = 2-24hrs. post- inhalation=> depending on the
magnitude of exposure: * massive intravascular hemolysis S x S: ..
malaise .. nausea .. hemogobinuria .. headache .. vomiting ..
dyspnea .. abdominal pain .. weakness .. jaundice
87. 8787 oliguric renal failure => consequence of Hb
deposition in the renal tubules .. appears w/in 3days massive
exposures => lethal effects on cellular respiration may occur
before renal failure develops =>urinary arsenic levels =
elevated .. seldom available to confirm dx
88. 8888 -> tx for arsine poisoning: => intensive
supportive care including: * exchange transfusion * vigorous
hydration * hemodialysis mainstay of therapy in case of renal
failure => chelating agents not yet demonstrated of clinical
value
89. 8989 Mercury -> metallic mercury- known as quicksilver
the only metal that is liquid under ordinary condition ->1950s
mercury = determined cause of : * birth defect Minamata *
neurologic diseases Japan causative agent = methyl mercury in
contaminated seafood => traced to industrial charges from a
nearby factory
90. 9090 -> forms of mercury causing clinical toxicity: *
elemental mercury * alkylmercury e.g. methylmercury * inorganic
mercury salts * aryl mercury compounds -> mercury = mined
predominantly as HgS in cinnabar ore variety of forms for different
applications sources of exposure
91. 9191 -> industrial and commercial application of
mercury: * electrolytic production of chlorine and caustic soda *
manufacture of electrical equipment, thermometers and other
instruments * fluorescent lamps * dental amalgam * artisanal gold
production
92. 9292 pharmaceutical use and use in biocides declined
significantly - occasional use in antiseptics and folk medicines
environmental mercury burning fossil fuels - bioaccumulation of
methylmercury in fish low-level exposure to mercury released from
dental amalgam fillings => systemic toxicity established
93. 9393 Pharmacokinetics of Mercury - absorption depends on
the chemical form -> elemental mercury quite volatile may be
absorbed from the lungs poorly absorbed from the intact GIT ->
inhaled mercury = 10 source of occupational exposure -> organic
short-chain alkylmercury cpds. - volatile potentially harmful by
inhalation and ingestion
94. 9494 -> percutaneous absorption of metallic and
inorganic mercury clinical concern ff. massive acute or long-term
chronic exposure -> alkylmercury compounds well absorbed through
the skin -> acute contact w/ few drops of dimethylHg severe
delayed toxicity - distribution of Hg: absorbed Hg few hrs. tissues
highest in the kidney
95. 9595 - excretion of hg: -> inorganic Hg excreted through
the urine and feces excretion follows multicomponent model
=>most excreted w/in wks.- mos. => fraction.. retained in the
kidneys and brain for years -> elemental Hg =>inhaled urinary
Hg level decline w/ ~ half-life = 1-3mos.
96. 9696 -> methylHg =>blood and whole body half-life ~
50days biliary excretion and enterohepatic circulation >2/3
excreted in the feces -> Hg + sulfhydryl groups in keratinized
tissue as in Pb2+ , As3+ hair and nails
97. 9797 Major forms of mercury intoxication - Hg interacts w/
sulfhydryl groups in vivo inhibits enzymes alters cell membranes -
factors that affect pattern of clinical intoxication from Hg: *
chemical form of the metal * route of exposure * severity of
exposure
98. 9898 acute intoxication - inhalation of elemental Hg vapor
causes: * chemical pneumonitis * noncardiogenic pulmonary edema *
acute gingivostomatitis * neurologic sequelae - ingestion of
inorganic Hg salts e.g. HgCl2 corrosive, potentially life
threatening hemorrhagic gastroenteritis followed w/in hrs.- days
by: acute tubular necrosis and oliguric renal failure
99. 9999 chronic intoxication - inhalation of Hg vapor results
in: * classic triad of tremor = hands = face = choreiform movements
of the limbs * neuropsychiatric manifestations = memory loss =
fatigue = insomnia = anorexia = change in mood -> shyness ->
w/drawal -> depression along w/ explosive anger or blushing
(erethism)
100. 100100 = low-dose exposure -> produce subclinical
neurologic effects * gingivostomatitis -> high-dose exposure to
Hg -> sometimes accompanied by loosening of teeth * overt
peripheral neuropathy = rare = peripheral nerve damage ->
detected by electrodiagnostic testing * acrodynia - uncommon
idiosyncratic reaction to subacute or chronic Hg exposure - occurs
mainly in children
101. 101101 - acrodynia is characterized by: -> painful
erythema of the extremities associated w/: .. HPN .. insomnia ..
diaphoresis .. irritability or apathy .. anorexia .. miliarial rash
methyl Hg intoxication affects mainly the CNS and results in: ->
paresthesias -> dysarthria -> ataxia -> progressive ->
hearing impairment constriction of the visual fields
102. 102102 - S x S -> appear several wks. or mos. After
exposure begins -> methyl Hg= reproductive toxin = high dose
prenatal exposure mental retardation offspring cerebral palsy-like
syndrome = low-level prenatal exposures assoc. w/ a risk of
subclinical neurodevelopment deficits - dimethyl Hg -> rarely
encountered -> extremely neurotoxic = lethal in small
quantities
103. 103103 - dx of Hg intoxication=> integration of : *
history * physical findings * laboratory > confirmatory test
-> w/o occupational exposure ..urine Hg concentration <
5mcg/L ..whole blood Hg < 5mcg/L -> 1990 => Biological
Exposure Index (BEI) committee recommended : ..workplace exposures
urine conc. < 35mcg/g of creatinine
104. 104104 end-of-work wk whole blood Hg to minimize risk from
methyl Hg: avoid consumption of fish w/ high Hg levels e.g.
swordfish limit consumption of fish w/ lower levels of Hg => to
no more than 12ounces = 340g. or two average meals/wk. ..to
minimize risk should be in particular among: * pregnant women *
women who might become pregnant * nursing mothers * young
children
105. 105105 - treatment of Hg poisoning: acute poisoning *
intensive supportive care * prompt chelation w/: -> oral or
intravenous unithiol -> I.M. dimercaprol -> oral succimer -of
value in diminishing nephrotoxicity after acute exposure to
inorganic Hg salts * vigorous hydration- help to maintain urine
output
106. 106106 * days or weeks of hemodialysis or hemodiafilration
in conjunction w/ chelation - necessary if acute renal failure
occurs - tx should not be delayed until the onset of uliguria or
other major systemic effects
107. 107107 chronic exposure -> unithiol and succimer
increase urine Hg excretion after acute or chronic inhalation of
elemental Hg impact on clinical outcome = ? -> succimer,
unithiol and N-acetyl- L- cysteine (NAC) enhance body clearance of
methyl Hg -> dimercaprol redistribute Hg to the CNS from other
tissues brain = target organ not used to tx exposure to elemental
or organic Hg
108. 108108 Chelators - drugs used to: * prevent or reverse
toxic effects of heavy metals on enzymes or other cellular target *
accelerate the elimination of the metal from the body - chelating
agents are flexible molecules two or more electronegative groups
form stable coordinate covalent bond w/ a cation metal atom
109. 109109 e.g. succimer parent compound in vivo
biotransformation active complexing agent excreted by the body Salt
and chelate formation with edetate (ethylenediaminetetraacetate,
EDTA) i.e. a) soln of Na2 salt of EDTA the Na+ & H+ ions =
chemically and biologically available b) soln of CaNa2 edetate
calcium is bound by coordinate covalent bonds with nitrogens as
well as by the usual ionic bonds
110. 110110 c) in the lead chelate lead is incorporated into
five heterocyclic rings - efficiency of chelator may be determined
by: number of ligand groups on the molecule available for metal
binding more ligand groups more stable the metal-chelator complex
complex may be referred to as * mono depending on the * bi # of
metal-ligand * poly dentate bonds
111. 111111 Effects of metal binding of chelating agents:
Prevents interaction of the metal with similar functional groups
of: enzymes coenzymes cellular neutrophiles membranes May enhance
the excretion of essential cations such as zinc or copper a side
effect which is seldom of clinical significance due to limited time
of chelation course e.g. Ca EDTA in lead intoxication
112. 112112 Metal-mobilizing effect of a therapeutic chelating
agent redistribute some of the metal to other vital organs e.g.*
dimercaprol - redistributes Hg & As to the brain - enhances
urinary Hg & As excretion * other chelating agent redistribute
Cd to the kidneyincrease nephrotoxicity negate therapeutic value
for Cd chelation - capacity of chelating agent in preventing toxic
effect of metals greatest if administered very soon after
exposure
113. 113113 Most commonly use chelating agents: Dimercaprol
(2,3 Dimercaptopropanol, BAL) - aqueous soln of dimercaprol is
unstable and readily oxidizedispensed in 10% peanut oil must be
adm. I.M.painful - action of dimercaprol: * animal models prevents
and reverses arsenic induced inhibition of sulfhydyl containing
enzymes if BAL is given soon after exposure, lethal effects of
inorganic & organic arsenicals may be prevented * human
increases excretion of As & Pb therapeutic benefit for As, Pb
& Hg intoxication
114. 114114 Indications of BAL - used as a single-agent
treatment for acute poisoning by: arsenic inorganic mercury severe
lead poisoning when used ih conjunction with edetate calcium
disodium - in human: adm. = I.M. readily absorbed metabolized and
excreted by the kidney within 4-8hrs bIliary excretion = uncertain
- animal models => biliary excretion is indicated
115. 115115 - adverse effects of BAL: therapeutic dose * HPN *
tachycardia * vomiting * lacrimation * salivation * fever
particularly in children * pain in the injection site * I.M. adm.
risk of hematoma formation thrombocytopenia increase prothrombin
time in acutely intoxicated animals BAL may redistribute As &
Hg to the CNS =>
116. 116116 * not advocated for chronic intoxication treatment
* replaced by : > unithiol water analogs of > succimer BAL =
higher therapeutic indices
117. 117117 Succimer (Dimercaptosuccinic Acidd, DMSA)
therapeutic use: * in animals - protect acute lethal effects of
arsenic poisoning succimer prevents and reverse metal induced
inhibition of sulfhydryl-containing enzymes * in human increase
urinary lead excretion - decrease in blood lead concentration -
decrease the Hg content of the kidney => key target organ of
inorganic Hg salts - U.S. => only oral formulation - all
others=> I.V. formulation = successfully used
118. 118118 - absorbed rapidly but variably after oral
adminiatration - peak blood level ~ 3hrs. i.e. succimer + cysteine
1:1 & 1:2 mixed disulfides in the kidney active chelating
moieties elimination half-time = 2-4 hrs. indication & toxicity
of succimer - use for the treatment of Pb poisoning: * children
with Pb conc. >45mcg/ml. * adults Pb poisoning usual dosage
=10mg/kg orally 3x/day
119. 119119 succimer indications & toxicity oral
administration of succimer: > comparable to parenteral EDTA in
reducing blood lead concentration > supplanted EDTA in
outpatient tx of patients capable of absorbing the drug - treat As
& Hg poisoning: * has a protective effect against As in animals
* has the ability to mobilize Hg from the kidney * limited clinical
trials showed DMSA = well tolerated
120. 120120 * negligible impact on body stores of calcium, iron
and magnesium * induces a mild increase in urinary zinc minor or no
clinical significance - toxicity of DMSA: * gastrointestinal
disturbances > anorexia > nausea most common vomiting
patients > diarrhea * rashes may require discontinuation of the
medication > intracellular ions EDTA penetrates cell membranes
relatively poorly - EDTA = highly polar limits its oral absorption
- oral adm. may increase Pb absorption from the gut
122. 122122 - EDTA rapidly excreted by glomerular filtration in
normal renal fxn 50% of injected is in the urine in 1hr. mobilizes
lead from soft tissues => marked increase in urinary lead
excretion => decline in blood lead concentration - indication of
EDTA: chelator of: * lead * zinc * manganese * certain heavy
radionuclides like uranium plutonium, americium and curium
123. 123123 analogs of EDTA used to remove uranium and certain
transuranic radioisotopes: > calcium disodium salts of
diethylene- > zinc triaminepentaacetic acid (DTPA), pentetate
contraindicated in anuric patients low doses of EDTA + hemodialysis
or hemofiltration = used toxicity of EDTA: * nephrotoxicity
prevented by: > adequate urine flow > avoidance of excessive
doses > limitation of treatment course to 80% of dose =>
excreted in the urine mainly as cyclic DMPS sulfides - elimination
half-time of total unithiol administered ~ 20hrs - in animal
models: exhibits protective effects against Hg & As toxic
action - in human: increase excretion of Hg, As & Pb
125. 125125 Penicillamine (D-Dimethylcysteine) - white
crystalline - water-soluble derivative of penicillamine -
D-Penicillamine < L-Penicillamine in toxicity more preferred
therapeutic form - readily absorb from the gut - resistant
tometabolic degradation - chiefly used : * for the treatment of
copper poisoning * prevent copper accumulation Wilsons disease
=> hepatolenticular degeneration * occassionally use to tx
severe
126. 126126 * increases urinary excretion of Pb & Hg may be
used to treat intoxication by these metals now replaced by
succcimer - toxicity : * hypersensitivity * nephrotoxicity with
proteinuria * pancytopenia associated with prolonged drug intake
Deferoxamine Deferasirox
127. 127127 Prussian Blue (Ferric Hexacyanoferrate) - has high
affinity for univalent cations such as: cesium thallium - used as
an oral drug - insoluble form undergoes minimal GIT absorption CNS
depressant > injury of liver, kidney and heart >
carcinogenicity due to CCl4, CCl3, trichloethylene and
tetrachloroethylene
132. 132132 * Human CNS depressant . CCl3 most potent - widely
used as anesthetic agent . Tetrachloethylene chronic exposure -
impaired memory - peripheral neuropathy . 1,1,1 trichloroethane
depressing agent . CCl4 most potent hepatotoxic agent . CCl4, CCl3
& trichloroethylene - nephrotoxicity
133. 133133 Carcinogenicity effects of low-level long term
exposure -Trichloroethylene environmental exposure - CCl3 household
exposure very large margin of safety for human Treatment for Acute
Intoxication of Halogenated Aliphatic H-C: No specific treatment
Management depends on the organ system
134. 134134 AROMATIC HYDROCARBONS * Benzene Uses : -- as
solvent -- intermediate in the synthesis of other chemicals --
TLV-TWA = 0.5ppm; TLV-STEL = 2.5ppm Acute Toxic Effect of Benzene:
-- Depression of the CNS
135. 135135 * Exposure to 7500ppm for 30 mins. = fatal *
>3000ppm causes: - Euphoria - Nausea - Locomotor problems - Coma
250 500ppm.= vertigo, drowsiness, headache and nausea
136. 136136 Chronic Exposure to Benzene: -- insidious to
unpredictable injury of the bone marrow -- aplastic anemia --
leukopenia -- pancytopenia -- thrombocytopenia -- leukemia * Bone
marrow cells in early development stage = most sensitive to
benzene
137. 137137 * Early symptoms of benzene intoxication: --
headache -- fatigue -- loss of appetite Treatment for acute benzene
intoxication- no specific treatment recommended
138. 138138 * Toluene - Methylbenzene - CNS depressant -
Difference from that of benzene -> No myelotoxic properties as
that of benzene -> Not associated with leukemia - TLV-TWA =
50ppm.; TLV-STEL = NA - Acute Exposure Effect: -> 800ppm =severe
fatigue and ataxia -> 10,000ppm. = rapid loss of
consciousness
139. 139139 INSECTICIDES
140. 140140 Organochlorine Insecticide include the ff: > DDT
(Chlorophenothane) and analogs poorly absorbed in the skin >
Benzene hexachlorides > Cyclodienes e.g. dielderin very
efficiently absorbed in the skin > Toxaphenes
141. 141141 Mechanism Action of Organochlorine: >
Organochlorine interfere w/ inactivation of the sodium channel in
excitable membranes cause rapid repetitive firing in most neurons
Calcium ion transport is inhibited affect repolarization and
enhance the excitability of neurons major effect = CNS
stimulation
142. 142142 S X S of Organochlorine intoxication: W/ DDT =
tremor = Convulsions W/ other compounds convulsion =first sign of
intoxication Treatment of Organochlorine Intoxication: - No
specific treatment had yet been establish for acute organochlorine
poisoning
143. 143143 Environmental Toxicology of Organochlorine: *
persistent chemicals * degradation - quite slow * bioaccumulate -
particularly in aquatic eco- systems * mobility in soil ->
presence of organic matter favors adsorption onto the soil ->
sandy soils adsorption is poor - once adsorbed > do not readily
desorbed
144. 144144 Organophosphorus Insecticide Dangerous to human and
highly effective as insecticide Biotransformation = rapid Less
stable than carbamates when dissolved in water thus have limited
half-life in the environment compared to halogenated
hydrocarbons
145. 145145 Absorption of Organophosphorus Except
Echothiophate: * Skin * Conjunctiva * Respiratory tract * CNS * GIT
Human Toxicology of Orgonophosphorus: * Mechanism of action
inhibition of acetyl- cholinesterase through phosphorylation of the
esteratic site- known to be cholinesterase inhibitors
146. 146146 S X S for acute intoxication of Organophosphorus:
> accumulation of acetylcholine > some of the agents possess
direct cholinergic activity > altered neurologic and cognitive
function > psychological symptoms caused by exposure to high
concentration > Organophosphorus ester-induced delayed
polyneuropathy (OPIDP particularly sensitive are hens
147. 147147 > Human : neurotoxicity particularly observed w/
the used of triortho-cresyl phosphate such as: .. dichlorvos ..
mipalox .. trichlorfon .. leptophos .. methamidophos ..
trichloronat
148. 148148 Thiophosphates are quite lipid-soluble - Absorbed
by all routes - Activated in the body by conversion to the oxygen
analogs- occurs both in insects and vertebrate -- Parathion and a
few other organophosphate insecticides rapidly metabolized by other
pathways to inactive products in birds and mammals but not
insects
149. 149149 safe enough for sale in gen. public - not
detoxified by fish -- Parathion- not detoxified effectively in
vertebrates - more dangerous than malathion to human and livestocks
and is not available for public use
150. 150150 Organophosphates - cholinesterase inhibitors -
initial signs of acute intoxication manifest those of muscarinic
excess * meiosis * salivation * sweating * bronchial constriction *
vomiting * diarrhea > CNS involvement accompanied by peripheral
nicotinic effect especially depolarizing neuromuscular
blockade
151. 151151 Therapy of Organophosphate Acute Intoxication:
Maintenance of vital signs respiration in particular may be
impaired Decontamination to prevent further absorption > remove
all clothing > washing of the skin in cases of exposure to dust
and sprays Atropine parenterally administered in large dose given
as required to control signs of muscarinic excess
152. 152152 Treatment: Severe Organophosphate Poisoning:
Tertiary amine e.g atropine must be used treats both the CNS and
peripheral effects of organophosphate inhibitors - dose * Parathion
& chemical warfare nerve gases = 1 2 mg. of atropine sulfate;
given intravenously every 5 15 mins. Until signs of effects such
as: dry mouth,
153. 153153 .. atropine administration may have to be repeated
many times acute effects of cholinesterase agents may last for 24
48 hrs. or longer .. 1 gm. of atropine/day given for as long as 1
mo. to fully control muscarinic xs Cholinesterase regenerator
compounds involves: regeneration of active enzyme from the
organophosphorus-cholinesterase complex to form oxime agents
(=NOH)
154. 154154 * Pralidoxime (PAM) most studied in human - only
one available for clinical use in U.S.A. - most effective in
regenerating the cholinesterase associated w/ skeletal muscle
neuromuscular junctions - ineffective in reversing the central
effect of organophosphate poisoning its positive charge prevents
entry into the CNS - administered by I.V. , 1-2gms. given over
15-30 mins.
155. 155155 - excessive doses of PAM can induce the ff.: >
neuromuscular weakness > other adverse effects observed - not
recommended to reverse inhibition of cholinesterase by carbamate
inhibitors Diacetylmonoxime (DAM) crosses the blood- brain barrier
- in animals can regenerate some of the central CNS
cholinesterase
156. 156156 Pretreatment w/ reversible enzyme inhibitors to
prevent binding of irreversible organophosphate inhibitor e.g.
pyridostigmine pysostigmine => reserved only wherein lethal
poisoning is anticipated e.g chemical warfare => simultaneous
use of atropine is required to control muscarinic excess
157. 157157 Carbamate Insecticides - inhibit
acetylcholinesterase by carbamoylation of the esteratic site -
non-persistent pesticides => small impact on the environment -
Clinical effects: > similar to organophosphate but of shorter
duration > the range between doses causing intoxication and
lethality is larger in carbamates than w/ organophosphates
158. 158158 > compared to organophosphate reactivation of
cholinesterase is more rapid after inhibition by carbamates >
carbamates are referred to as reversible cholinesterase inhibitors
organophosphates irreversible cholinesterase inhibitors - Treatment
of Carbamate Poisoning: > Similar to that of organophosphate
poisoning but PAM is not recommended
159. 159159 BOTANICAL INSECTICIDES Derived from natural sources
It includes the ff.: * Nicotine from Nicotiana tabacum N rustica *
Rotenone * Pyrethrum
160. 160160 NICOTINE Absorption: > Free alkaloid but not the
salt readily absorbed from the skin Mechanism of action: >
Nicotine reacts w/ acetylcholine receptor of the postsynaptic
membrane i.e. sympathetic and parasympathetic ganglia,
neuromuscular junction---> depolarization of
161. 161161 the mucous membrane --->Toxic doses cause
stimulation rapidly followed by blockade of transmission Treatment:
> Maintenance of vital sign > Suppression of convulsion
163. 163163 PYRETHRUM Includes: > Pyrethrin I > Cinerin
II > Pyrethrin II > Jasmolin I > Cinerin I > Jasmolin I
Esters are extensively biotransformed Highly toxic to mammals Major
site of toxic action = CNS Absorption = ingestion, inhalation and
skin not significant
164. 164164 > Excitation > contact dermatitis >
Tetanus paralysis >cutaneous paresthesias > Convulsions
Targets of Pyrethrum: > Voltage gated sodium channel Toxic
Effects of Pyrethrum Insecticides: > Voltage gated calcium
channel > Voltage gated chloride channel > Peripheraltype
benzodiazepine receptor
165. 165165 Treatment for Pyrethrum Intoxication: >
symptomatic treatment is employed > anticonvulsants = not
consistently effective > chloride channel agonist: * ivermectin
* pentobarbital * mephenesin
167. 167167 Human Toxicity Effects: > 2,4-D coma muscle
hypotonia > 2,4,5-T coma muscular dysfunction occupational
exposure=> associated w/ increased risk of Non-Hodgkins
lymphoma
168. 168168 Soft tissue sarcoma = equivocally suspected Pls.
note: - Care in establishing toxicological profile especially
2,4,5-T => intoxication can be caused by contaminants most
important of w/c is Tetrachlorodibenzo-p-dioxin (TCDD)
169. 169169 2. Bipyridyl Herbicides * Paraquat most important
agent of bipyridyl herbicides .. mechanism of action: > involves
single electron reduction of the herbicide to free radical species
.. toxicity rating = 4 Human lethal dose = 50- 500 mg/kg
170. 170170 Toxicity Effects of Paraquat: - Accumulates slowly
in the lungs by an active process causing: > lung edema >
alveolitis > progressive fibrosis - S X S in human: > after
oral ingestion .. GIT irritation=> hematemesis, bloody
171. 171171 > Delayed Toxicity: .. Respiratory distress ..
Congestive hemorrhagic pulmonary edema .. Cellular proliferation ..
Hepatic, renal or cardiac involvement .. Death several weeks after
ingestion Treatment of Paraquat Intoxication: > Prompt removal
of paraquat from GIT by: .. Use of gastric lavage .. Use of
cathartics
172. 172172 .. Use of adsorvent .. Oxygen should be used
cautiously to combat dyspnea or cyanosis- may aggravate the
pulmonary lessions .. Patients should be observed longer
proliferation phase begins 1-2 weeks after ingestion
173. 173173 Polychlorinated dibenzo-p-dioxin(PCDDs) or dioxins=
group of congeners of PCBs *
2,3,7,8-tetrachlorodibenzo-p-dioxins(TCDD) most important congener
* Polychlorinated dibenzofurans (PCDFs) * Coplanar biphenyls
dioxin-like cpds. .. TCDDs and PCDFs: - like PCBs = very stable =
highly lipophilic
174. 174174 = poorly metabolized = very resistant to
environmental degradation .. TCDDs effect in lab animals: - wasting
syndrome - thymic atrophy - epidermal changes - hepatotoxicity -
effects on reproduction and development - teratogenicity -
carcinogenicity
175. 175175 > effects observed in animals are not observed
in human > workers involved in manufacturing: .. 2,4,5-T perhaps
exposed to TCDD - contact dermatitis - chloracne .. Severely
TCDD-intoxicated patients = discrete chloracne > presence of
TCDD in 2,4,5-T = responsible for other human toxicities
176. 176176 2. Endocrine Disruptors: - chemicals that mimic or
enhance or inhibit a hormonal action - included are: * plant
constituents phytoestrogen * mycoestrogens * persistent
organochlorine- DDT, PCBs * brominated flame returdants -
Properties: bioaccumulation * potent toxicant * increasing
contamination of the environment