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110 Cards in this Set
- Front
- Back
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understood tx of poisons by altering absorption
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Hippocrates
400 BC |
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used condemned criminals to test for antidotes
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Nicander of Colophon
Greece 150 BC |
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categorized poisons:
animal plant mineral |
Dioscorides
50 BC |
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poisoning as an art form & political tool
(mainly arsenic) |
Borgias
1500s |
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spanish dr forensic toxicology & detection of poisons
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Orfila
1800s |
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the interpretation of dose-response relationship is based on what 3 factors:
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1. response proportional to conc. at target site
2. conc. at target site is related to dose 3. response is causally related to conc. administered |
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what shape is a typical dose-response curve when plotted?
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sigmoidal
(& response vs. log conc) |
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what is ED50?
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ED50 is the dose at 50% of maximum response
used for measuring compound efficacy dose is efficacious in 50% of the responses |
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what is TD50?
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TD50 measures toxic effects of the compound
determines doase that is toxic in 50% of the responses |
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what is LD50?
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LD50 uses lethality to determines doase that is lethal in 50% of the responses
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how do you compare potency?
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if you have two plots that have the same TD50, the one with the STEEPER slope is MORE POTENT
this means one sees toxic effects at lower conc. |
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what is LD50?
ethanol? DDT? Nicotine Tetradotoxin Dioxin |
ethanol? = 10,000 mg/kg
DDT? = 100mg/kg Nicotine? = 1mg/kg Tetradotoxin? = 0.1 Dioxin? = 0.001 |
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why does tox depend on route of administration?
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involves distribution & metabolism
up to 10x variation in LD50 for the same compound depending on route |
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explain calcuation of therapeutic index?
what does a larger TI ratio mean? |
can use either TD50 or LD50 as it relates to ED50
LD50 / ED50 TD50 / ED50 example Drug A TD = 100 mg ED = 10 mg ratio = 100 / 10 TI = 10 example Drug B TD = 60 mg ED = 30 mg ratio = 60 / 30 TI = 2 SO, THE LARGER THE RATIO, THE 'SAFER' THE DRUG TI is calculated the same way for Rx, OTC, poisons |
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what is NOAEL and what does it tell us?
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NOAEL
no observed adverse effect level this is a set amount (ex.. = 5mg) responses of drug BELOW the NOAEL = effect responses with NO adverse effects if a dose curve begins at NOAEL, there is no safe dose for that drug |
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ADI?
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measurement is based on NOAEL
ADI = acceptable daily intake level of compounds (food additives, pesticides, contaminants, etc) viewed as "acceptable" for daily consumtion without harm |
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TLV?
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measurement is based on NOAEL
TLV = threshold limit value determined acceptable exposure (industrial / occupational) for 8 hour work day |
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what is Vd?
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volume of distribution
= dose / plasma conc. (mg) / (mg/L) high VD, but low plasma conc. = storage in adipose tissue |
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what is the significance of plasma levels?
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plasma levels reflect conc at tissue better that dose amount would. and it may reflect conc. at target tissue
plasma levels are necessary to calc T1/2, VD, AUC, and WBB WBB = whole body burden AUC = area under curve AUC can give indication of time of significant exposure |
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what two things are determined from the linear portion of the curve? (Cp vs. time)
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T1/2
& elimination rate constate |
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what is 1st pass metab?
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metab by liver following absorption
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TBC
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total body clearance =
dose / AUC if there is a LARGER dose, but SMALL AUC = means that the drug is cleared QUICKLY |
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compare Drug A (24hr T1/2)
& Drug B (12hr T1/2) (graph) |
if the dosing is the same, the compound with twice the 1/2 life with be twice the average plasma concentration
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types of excretion
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urinary
lung biliary breast milk sweat tears semen stomach saliva |
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urinary excretion acid for active transport?
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active transport = p-aminohippuric acid
diffusion of blood into tubule is active or passive |
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biliary excretion is good for __?
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large polar molecules
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biliary excretion is an ___ process? (passive or active)
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active process (3 systems)
- neutral, + and - - saturable which may increase tox (ex. furosemide) - gut may convert to more active compound (enterohepatic recirculation, increase tox) (there is a pic of estrogen metab in book) |
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what are the 3 goals of metabolism?
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1. make compound more polar
2. increase molecular wt and size 3. facilitate excretion, elimination |
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what are some consequences of metabolism changes?
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- 1/2 life decreases
- body exposure time is shortened - accumulation is reduced - probable change in biological activity (inc OR dec) - change in duration of bio action - increased water solubility (may decrease in some cases, acetylation of sulfonamides decr sol & damages tubules) |
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what are the 2 phases of metabolism
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phase 1: add fxnal group to permit conjugation in phase 2 (ex- benzene + hydroyl = phenol)
phase 2: conjugation with large polar groups |
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what are the major rxns of phase 1?
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oxidation
reduction hydrolysis hydration dehydration |
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what are the major rxns of phase 2?
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sulfation
glucuronidation glutathione conjugation acetylation amino acid conjugation |
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what are the 4 major steps of P450 system (phase 1)
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step 1: addition of substrate
step 2: donation of electron step 3: addition of oxygen and rearangement step 4: donation of a second electron and loss of water |
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if a reactive metabolite has failure / overload of detox, what 3 things could happen?
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1. antigenic conjugation --> immune response
2. DNA damage --> mutation --> cancer 3. tissue damage --> necrosis |
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what factors can effect toxic responses?
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species, strain, gender, genetic/ethnic variables (fast vs. poor metabs, enxymes), environment, existing pathologies
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adverse effects of:
opioids |
opioids:
miotic pupils CNS / resp. depression |
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adverse effects of:
anticholingergics |
anticholingergics:
dry, flushed appearance mydriasis bowel atony hallucinations |
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adverse effects of:
cholinergics |
cholinergics:
muscarinic: salivation defecation lacrimation urination niotinic: mm. fasciculations weakness paralysis |
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adverse effects of:
stimulants |
tachycardia
HTN hyperthermia mydriasis agitation |
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adverse effects of:
TCAs |
anticholinergic symptons
EKG abnormalities |
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CO
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CO:
air pollutant, toxic gas produced by combustion colorless, non-irritating, avg conc = 0.1 ppm (heacy traffic > 100 ppm) |
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CO mechanism of action
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toxic mech of action:
--CO combines reversibly w/ hemoglobin 220x greater affinity than O2 normal, non-smokers = <1% sat carboxyhemoglobin smokers = 5-10% sat |
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CO poisoning
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list in increasing % sat:
HA, throbbing temples, severe HA, weakness, dizziness, dimness of vision, N/V, collapse (30%), syncope, increase resp & pulse, coma w convulsions, depressed cardio/resp fxn, possible death (60%), resp falure = death (80%) |
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clinical effets of CO toxicity
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HYPOXIA
-- psychomotor impairment -- HA and temporal tightness -- confusion & loss of visual act -- tachycardia, syncope, coma -- deep coma, shock, resp failure |
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tx of acute intoxication / poisoning of:
CO |
removal from CO
admin OXYGEN: room air = 320 min 100% O2 = 80 min hyperbaric O2 = 20 min (hyperbaric to tx CO is controversial, tho) |
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CN
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hydrogen cyanide
fumigant to kill bugs, also cyanide from ground almond pits, sterilize soil, released from burning of plastics inhibits cytochrome oxidase of Mt at the Fe site --> CYTOTOXIC HYPOXIA |
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clinical signs of CN poisoning
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hypoxia
loss of consciousness resp arrest: 5 min if inhaled 30 min if ingested |
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tx of acute intoxication / poisoning of:
CN |
cyanide kit:
-- sodium nitrite: used to convert Hg to metHg (ferric iron containing form) CN has high affinity for ferric iron, get cyanomethemoglibin --> thiocyanate -- sodium thiosulfate: used to facilitate formation of thiocyanate formation thiocyanate excr in urine |
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Lead
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lead poisoning = plumbism
decreased due to banning of lead paints, but mean blood Pb levels in children still 6 ug/dl tox batteries, toys, illicit alcohol, improper canning, & RETAINED BULLETS |
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which can be aborbed from skin? organic or inorganic lead?
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inorganic lead:
slowly but well absorbed from GI and inhalation, NOT VIA SKIN organic lead (tetraethyl lead): WELL ABSORBED FROM SKIN (remember: i only put ORGANIC lotion on MY SKIN) |
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mech of tox: Pb blood
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blood - Pb binds to RBCs, blocks heme syn, protoporphyrins in urine and blood
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what toxin in barbie tent pole? 101 dalmation backpack?
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barbie: lead
dalmation: cadmium |
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common central and peripheral affects of Pb
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wrist drop (ex. 60 yo house painter)
encephalopathy in children, starts w convulsions, increased intracranial pressure and brain edema |
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tx of encephalopathy in children Pb tox?
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prompt chelation therapy
FATAL WITHOUT |
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mech of tox: Pb kidney
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interstitial kidney damage and HTN, acute gout
(adult HTN, esp. in black males, may be due to envir Pb exposure as child |
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mech of tox: Pb
reproductive |
decreased fertility, increased still born
decreased sperm count |
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mech of tox: Pb
GI |
loss of appetite
epigastic distress colicky pain constipation |
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what is a sign in the mouth of Pb tox?
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see a blue line at gingival margin
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sign / symptoms of Pb vs conc in blood
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increasing conc:
12 - developmental tox, decreased IQ, growth, hearing, decr vit D metab, decr nerve conduction velocity, inc RBC protoporphyrins 50- decr Hg, inc urine protoporphyrins 100- death, encephalopathy, neuropathy, frank anemia, colic |
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Hg
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only metal liquid at rm temp
dental labs, spermicidal jellies, fireworks, batteries, thermometers |
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Hg pharmacokinetics
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Hg volative, absorbed after inhalation
variable abs by GI depending on form |
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mech of tox by Hg
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binding to sulfhydryl groups on enzymes / proteins
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major forms of Hg tox:
-acute -chronic |
acute: inhalation
chest pain, metallic taste, N/V, renal damage, severe gingivitis & GI, severe m. tremor & psychopathology KIDNEYS ARE THE FIRST ORGAN TO BE EFFECTED chronic: oral & GI, renal insufficiency, gingivitis & loose teeth, tremor may mimic: wilson's disease, cerebellar ALL ORGAN SYSTEMS ARE EFFECTED IN CHRONIC TOX |
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tx Hg & Pb tox
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chelator
versatile & efective antidotes for hvy metal tox flexible molecules w electronegative sites to form stable covalent bonds w cationic metal classed by # of sites that bind |
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what chelator was made to counter Lewisit, a WWII vesicant gas containing As?
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Dimercaprol (2,3- dimercaptopropanol) (BAL IN OIL)
unstable in H2O, mixed with 10% peanut oil, painful IM injections |
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what is Dimercaprol indicated for?
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antidote to arsenic, mercury, childhood lead tx, also cadmium
CAUTION used with Cd tx...may increase renal Cd conc leading to organ tox |
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BAL tx effects?
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HTN & tachycardia
HA, N/V, lacrimation, salivation, paraesthesias, pain at injection site |
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which chelator is approved for childhood Pb tx for blood levels > 45?
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Succimer (2,3 Dimercaptosuccinic acid)
also effective for As, Pb, Hg tox: MILD minor changes in liver enzymes and WBC count |
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which chelator is obtained from Streptomyces pilosus, fungal-like bacterium?
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Deferozamine
used for acute iron (Fe) tox, & chronic Fe tox (thalassemia) NOT USED FOR Pb, Hg, As, or Cd |
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chelator used mostly for LEAD?
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succimer
(2,3 dimercaptosuccinic acid) |
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chelator used for IRON? (ONLY IRON)
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Deferoxamine
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chelator used mostly for ARSENIC?
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Dimercaprol
(2,3 dimercaptopropanol) |
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which chelator should NOT be used with vit c?
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Deferoxamine
serious interaction!! (used for iron tox ONLY) |
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which chelator causes pain at injection site?
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Dimercaprol
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what is the Ames Test and what does it test for?
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mutagens!!
changes in DNA in vitro cell culture of genetically modified salmonella stain you should also test for: teratogens, carcinogens |
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what are the acute and chronic tox signs for ethanol?
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ethanol
acute = CNS depression chronic = liver cirrhosis |
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what are the acute and chronic tox signs for arsenic?
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arsenic
acute = GI damage chronic = skin / liver CA |
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non-tox, tox, lethal doses of alcohol
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non-tox = 0.05%
tox = 0.1% lethal = 0.5% |
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non-tox, tox, lethal doses of CO
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non-tox = <10%
tox = 20-30% lethal = > 60% |
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non-tox, tox, lethal doses of sleep aid secobaraital
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non-tox = 0.1
tox = 0.7 lethal = >1 |
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non-tox, tox, lethal doses of asp
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non-tox = 2 tab (0.65g)
tox = 30 tabs lethal = 105 tabs |
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non-tox, tox, lethal doses of ibuprofin
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non-tox = 2 tab (400mg)
tox = 7 tabs lethal = 60 tabs |
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types of mixtures and effects of tox..
additive antagonistic potentiation synergistic |
add = 20 + 30 = 50
antag = 20 + 30 = 5 potentiation = 0 + 20 = 50 synergism = 5 + 10 = 100 |
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when do you NOT use emesis to tx poison?
(syrup of ipecac) |
corrosive acid or base, pts comatose can get aspiration
CNS stimulant = seizures hydrocarbon = aspiration --> chem pneumo |
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activated charcoal ratio given?
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10:1 charcoal: poison ratio
decreases GI abs NOT given with ipecac |
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what are the top 5 poisoning substances
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1. household cleaning products
drain cleaners, bleach 2. cosmetics polish remover, mouthwash 3. plants wild mushrooms, flowers, roots 4. hydrocarbons butane (inhaled abuse) 5. chemicals ethylene glycol (antifreeze) MC |
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how is hematopoietic toxicity measured?
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cell counts
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what drug causes hematopoietic tox and what does it cause? TQ?
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chloramphenicol
attacks bone marrow & blocks Fe2+ into heme causes: agranulocytosis anemia |
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how is hepatocellular toxicity measured?
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serum transaminase levels
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what drugs cause hepatotox and what does it cause? TQ?
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acetaminophen
isoniazid troglitazone |
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drugs what cause nephrotoxicity?
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cisplatin
administer with large volumes to keep drug dilute in tubules usually shows as DECREASED CLEARANCE elevates plasma drug levels |
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what kind of pulmonary tox do opiods cause?
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respiratory depression
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what kind of pulmonary tox do bleomycin & amiodarone cause?
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pulmonary fibrosis
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what drug causes cardiotox what resembles CHF?
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Doxorubicin
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what type of drug interaction:
altered drug absorption? |
interactions with food
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what type of drug interaction:
chemical rxn btwn drugs |
pharmaceutical
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what type of drug interaction:
additive, synergistic, antag? |
pharmacodynamic
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what type of drug interaction:
altered gut motility or secretion, binding or chelation of drugs, competition for active transport |
pharmacokinetics:
altered drug absorption |
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what type of drug interaction:
displacement from plasma protein-binding ites, displacement from tissue-binding site |
pharmacokinetics:
altered drug distribution |
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what type of drug interaction:
altered hepatic blood flow, enxyme induction or inhibition |
pharmacokinetics:
altered drug biotransformation |
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what type of drug interaction:
altered biliary excretion or enterohepatic cycling, altered urine pH, drug-induced renal impairment, inhibition of active tubular secretion |
pharmacokinetics:
altered drug excretion |
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what type of drug interaction:
chem rxn PRIOR to administration |
pharmaceutical (usually drugs that need to be mixed before administering)
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what kind of drugs are effected by gender?
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HIV agents
antiarrhythmic agents anesthetics due mostly to differences in mass, TBW |
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what CYP do WOMEN have higher activity of?
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CYP 3A
> 50% of drugs are metabolized by CYP3A increased activity = decr drug effectiveness females CLEAR these drugs FASTER |
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what pump is higher in men?
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P-gp drug efflux pump encoded by MDR1 gene = higher in men
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which CYPs metabolize >80% of drugs today? CQ
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CYP 2D6
CYP 2C19 CYP 2C9 |
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variation in CYP 2D6
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poor metabolizers
lack activity "ultra-rapid" metabolizers opiates, TCA, some antipsychotics |
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variation in CYP 2C19 activity effects what drugs?
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benzos
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CYP 3A4 drugs?
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antineoplastic agents, benzos, statins, beta-antagonist
(remember, women have higher 3A) |
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are polymorphisms confined to phase I rxns?
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NO-
some conjugations have been identified |
