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110 Cards in this Set

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understood tx of poisons by altering absorption
Hippocrates
400 BC
used condemned criminals to test for antidotes
Nicander of Colophon
Greece
150 BC
categorized poisons:
animal
plant
mineral
Dioscorides
50 BC
poisoning as an art form & political tool
(mainly arsenic)
Borgias
1500s
spanish dr forensic toxicology & detection of poisons
Orfila
1800s
the interpretation of dose-response relationship is based on what 3 factors:
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
what shape is a typical dose-response curve when plotted?
sigmoidal
(& response vs. log conc)
what is ED50?
ED50 is the dose at 50% of maximum response

used for measuring compound efficacy

dose is efficacious in 50% of the responses
what is TD50?
TD50 measures toxic effects of the compound

determines doase that is toxic in 50% of the responses
what is LD50?
LD50 uses lethality to determines doase that is lethal in 50% of the responses
how do you compare potency?
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.
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
why does tox depend on route of administration?
involves distribution & metabolism

up to 10x variation in LD50 for the same compound depending on route
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
what is NOAEL and what does it tell us?
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
ADI?
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
TLV?
measurement is based on NOAEL

TLV = threshold limit value

determined acceptable exposure (industrial / occupational) for 8 hour work day
what is Vd?
volume of distribution
=
dose / plasma conc.
(mg) / (mg/L)

high VD, but low plasma conc. = storage in adipose tissue
what is the significance of plasma levels?
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
what two things are determined from the linear portion of the curve? (Cp vs. time)
T1/2
&
elimination rate constate
what is 1st pass metab?
metab by liver following absorption
TBC
total body clearance =
dose / AUC

if there is a LARGER dose, but SMALL AUC = means that the drug is cleared QUICKLY
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
types of excretion
urinary
lung
biliary
breast milk
sweat
tears
semen
stomach
saliva
urinary excretion acid for active transport?
active transport = p-aminohippuric acid

diffusion of blood into tubule is active or passive
biliary excretion is good for __?
large polar molecules
biliary excretion is an ___ process? (passive or active)
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)
what are the 3 goals of metabolism?
1. make compound more polar
2. increase molecular wt and size
3. facilitate excretion, elimination
what are some consequences of metabolism changes?
- 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)
what are the 2 phases of metabolism
phase 1: add fxnal group to permit conjugation in phase 2 (ex- benzene + hydroyl = phenol)

phase 2: conjugation with large polar groups
what are the major rxns of phase 1?
oxidation
reduction
hydrolysis
hydration
dehydration
what are the major rxns of phase 2?
sulfation
glucuronidation
glutathione conjugation
acetylation
amino acid conjugation
what are the 4 major steps of P450 system (phase 1)
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
if a reactive metabolite has failure / overload of detox, what 3 things could happen?
1. antigenic conjugation --> immune response

2. DNA damage --> mutation --> cancer

3. tissue damage --> necrosis
what factors can effect toxic responses?
species, strain, gender, genetic/ethnic variables (fast vs. poor metabs, enxymes), environment, existing pathologies
adverse effects of:
opioids
opioids:
miotic pupils
CNS / resp. depression
adverse effects of:
anticholingergics
anticholingergics:
dry, flushed appearance
mydriasis
bowel atony
hallucinations
adverse effects of:
cholinergics
cholinergics:
muscarinic:
salivation
defecation
lacrimation
urination

niotinic:
mm. fasciculations
weakness
paralysis
adverse effects of:
stimulants
tachycardia
HTN
hyperthermia
mydriasis
agitation
adverse effects of:
TCAs
anticholinergic symptons
EKG abnormalities
CO
CO:
air pollutant, toxic gas produced by combustion

colorless, non-irritating, avg conc = 0.1 ppm (heacy traffic > 100 ppm)
CO mechanism of action
toxic mech of action:
--CO combines reversibly w/ hemoglobin 220x greater affinity than O2

normal, non-smokers = <1% sat carboxyhemoglobin

smokers = 5-10% sat
CO poisoning
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%)
clinical effets of CO toxicity
HYPOXIA

-- psychomotor impairment
-- HA and temporal tightness
-- confusion & loss of visual act
-- tachycardia, syncope, coma
-- deep coma, shock, resp failure
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)
CN
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
clinical signs of CN poisoning
hypoxia
loss of consciousness
resp arrest:
5 min if inhaled
30 min if ingested
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
Lead
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
which can be aborbed from skin? organic or inorganic lead?
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)
mech of tox: Pb blood
blood - Pb binds to RBCs, blocks heme syn, protoporphyrins in urine and blood
what toxin in barbie tent pole? 101 dalmation backpack?
barbie: lead
dalmation: cadmium
common central and peripheral affects of Pb
wrist drop (ex. 60 yo house painter)

encephalopathy in children, starts w convulsions, increased intracranial pressure and brain edema
tx of encephalopathy in children Pb tox?
prompt chelation therapy
FATAL WITHOUT
mech of tox: Pb kidney
interstitial kidney damage and HTN, acute gout

(adult HTN, esp. in black males, may be due to envir Pb exposure as child
mech of tox: Pb
reproductive
decreased fertility, increased still born

decreased sperm count
mech of tox: Pb
GI
loss of appetite
epigastic distress
colicky pain
constipation
what is a sign in the mouth of Pb tox?
see a blue line at gingival margin
sign / symptoms of Pb vs conc in blood
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
Hg
only metal liquid at rm temp

dental labs, spermicidal jellies, fireworks, batteries, thermometers
Hg pharmacokinetics
Hg volative, absorbed after inhalation

variable abs by GI depending on form
mech of tox by Hg
binding to sulfhydryl groups on enzymes / proteins
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
tx Hg & Pb tox
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
what chelator was made to counter Lewisit, a WWII vesicant gas containing As?
Dimercaprol (2,3- dimercaptopropanol) (BAL IN OIL)

unstable in H2O, mixed with 10% peanut oil, painful IM injections
what is Dimercaprol indicated for?
antidote to arsenic, mercury, childhood lead tx, also cadmium

CAUTION used with Cd tx...may increase renal Cd conc leading to organ tox
BAL tx effects?
HTN & tachycardia
HA, N/V, lacrimation, salivation, paraesthesias, pain at injection site
which chelator is approved for childhood Pb tx for blood levels > 45?
Succimer (2,3 Dimercaptosuccinic acid)

also effective for As, Pb, Hg

tox: MILD
minor changes in liver enzymes and WBC count
which chelator is obtained from Streptomyces pilosus, fungal-like bacterium?
Deferozamine

used for acute iron (Fe) tox,
& chronic Fe tox (thalassemia)

NOT USED FOR Pb, Hg, As, or Cd
chelator used mostly for LEAD?
succimer
(2,3 dimercaptosuccinic acid)
chelator used for IRON? (ONLY IRON)
Deferoxamine
chelator used mostly for ARSENIC?
Dimercaprol
(2,3 dimercaptopropanol)
which chelator should NOT be used with vit c?
Deferoxamine
serious interaction!!

(used for iron tox ONLY)
which chelator causes pain at injection site?
Dimercaprol
what is the Ames Test and what does it test for?
mutagens!!
changes in DNA
in vitro cell culture of genetically modified salmonella stain

you should also test for:
teratogens, carcinogens
what are the acute and chronic tox signs for ethanol?
ethanol

acute = CNS depression
chronic = liver cirrhosis
what are the acute and chronic tox signs for arsenic?
arsenic

acute = GI damage
chronic = skin / liver CA
non-tox, tox, lethal doses of alcohol
non-tox = 0.05%
tox = 0.1%
lethal = 0.5%
non-tox, tox, lethal doses of CO
non-tox = <10%
tox = 20-30%
lethal = > 60%
non-tox, tox, lethal doses of sleep aid secobaraital
non-tox = 0.1
tox = 0.7
lethal = >1
non-tox, tox, lethal doses of asp
non-tox = 2 tab (0.65g)
tox = 30 tabs
lethal = 105 tabs
non-tox, tox, lethal doses of ibuprofin
non-tox = 2 tab (400mg)
tox = 7 tabs
lethal = 60 tabs
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
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
activated charcoal ratio given?
10:1 charcoal: poison ratio
decreases GI abs

NOT given with ipecac
what are the top 5 poisoning substances
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
how is hematopoietic toxicity measured?
cell counts
what drug causes hematopoietic tox and what does it cause? TQ?
chloramphenicol
attacks bone marrow & blocks Fe2+ into heme

causes:
agranulocytosis
anemia
how is hepatocellular toxicity measured?
serum transaminase levels
what drugs cause hepatotox and what does it cause? TQ?
acetaminophen
isoniazid
troglitazone
drugs what cause nephrotoxicity?
cisplatin
administer with large volumes to keep drug dilute in tubules

usually shows as DECREASED CLEARANCE
elevates plasma drug levels
what kind of pulmonary tox do opiods cause?
respiratory depression
what kind of pulmonary tox do bleomycin & amiodarone cause?
pulmonary fibrosis
what drug causes cardiotox what resembles CHF?
Doxorubicin
what type of drug interaction:
altered drug absorption?
interactions with food
what type of drug interaction:
chemical rxn btwn drugs
pharmaceutical
what type of drug interaction:
additive, synergistic, antag?
pharmacodynamic
what type of drug interaction:
altered gut motility or secretion,
binding or chelation of drugs,
competition for active transport
pharmacokinetics:
altered drug absorption
what type of drug interaction:
displacement from plasma protein-binding ites,
displacement from tissue-binding site
pharmacokinetics:
altered drug distribution
what type of drug interaction:
altered hepatic blood flow,
enxyme induction or inhibition
pharmacokinetics:
altered drug biotransformation
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
what type of drug interaction:
chem rxn PRIOR to administration
pharmaceutical (usually drugs that need to be mixed before administering)
what kind of drugs are effected by gender?
HIV agents
antiarrhythmic agents
anesthetics

due mostly to differences in mass, TBW
what CYP do WOMEN have higher activity of?
CYP 3A
> 50% of drugs are metabolized by CYP3A
increased activity = decr drug effectiveness
females CLEAR these drugs FASTER
what pump is higher in men?
P-gp drug efflux pump encoded by MDR1 gene = higher in men
which CYPs metabolize >80% of drugs today? CQ
CYP 2D6
CYP 2C19
CYP 2C9
variation in CYP 2D6
poor metabolizers
lack activity
"ultra-rapid" metabolizers

opiates, TCA, some antipsychotics
variation in CYP 2C19 activity effects what drugs?
benzos
CYP 3A4 drugs?
antineoplastic agents, benzos, statins, beta-antagonist

(remember, women have higher 3A)
are polymorphisms confined to phase I rxns?
NO-
some conjugations have been identified