Toxicology

Exam 3

True or false: something that is non-toxic can be toxic

true

True or false: highly toxic chemicals can be life saving when given in appropriate doses

true

Explain the response curve

graphically represents the relationships between the dose of a drug and the response elicited

What is the shape of a dose response curve

sigmoidal 

The reaction to the dose is known as the ______-

response

True or false: the response is independent of the dose

False

True or false: the dose-response curve may differ for different populations

true

What is number 1?

low dose→ no observable response (subtherapuetic)

What happens at number 2?

increased dose → therapeutic response (and side effects)

What happens at number 3?

increased dose → therapeutic dose toxicities

What is at number 4?

the therapeutic window 

Key considerations in toxicity

1. routes of exposure

2. duration

3. exposure of mixtures

4. individual susceptibility

5. ADME

What are the 8 routes of exposure

1. oral (buccal/SL)

2. parenteral

3. topical/transdermal

4. rectal/vaginal

5. otic

6. ocular

7. nasal

8. inhalation

Rank the routes of exposure from most to least effic

Injection (IV) → inhalation → skin (absorption) → ingestion 

(could argue between placement of skin and ingestion)

Order of efficiency 

IV → inhalation → ip → im → topical → ingestion 

the ability of a chemical to enter the blood

absorption

The kinetics of absorption are altered by what

concentration of the drug

What is first order kinectics

A constant proportion of the drug is eliminated per unit of time

What is zero order kinectics

constatn amount of the drug is eliminated per unit of time

Which order kinetics is a concentration-dependent process and which is independent of concentration

dependent: first order

Independent: second 

storage where can lead to rapid mobilization of the fat and can rapidly increase blood concentration of mercury

adipose tissue (lipophilic compounds)

Biotransformation can result in the formation of reactive metabolites 

bioactivation

what is the primary objective of metabolism

make chemicals agents more water soluble and easier to excrete (detoxification)

NAPQI is toxic to what type of cells

hepatic cells

when glucuronide sites are saturated, the body makes more what 

NAPQI

How does NAC prevent Tylenol toxicity?

By increasing GSH levels

Role of glutathione

neutralize NAPQI to generate non-toxic cysteine and mercapturic acid conjugates

Overdoses on APAP depletes _____ resulting in an increase in NAQI

GSH

NAQI will start interacting with the _____ groups on proteins, especially enzymes (overdose)

SH

How are water soluble products excreted?

filtered out by the blood by kidneys and excreted into urine

how can elimination be enhanced with some toxicants

• changing the pH of the urine

• increasing urine flow

• increased blood volume

why is drinking alcohol and taking APAP so toxic?

alcohol decreases GSH levels

alcohol (increases/decreases) CYP450?

increase

Alcohol generates (more/less) NAQI

more

Alcohol uses up liver ___

GSH

Alcohol and APAP rapidly accelerates ______ 

hepatic necrosis 

True or false: toxicity of alcohol and APAP can be seen the day after

True

What neutralizes NAPQI

Glutathione

Alcohol (increases/decreases) CYP 450

Increases

Alcohol decreases _____

GSH levels

Which heavy metal causes CNS deficits, anemia, hypertension and reproductive toxicity?

Lead

Which heavy metal causes cardiovascular shock, peripheral neuropathy and cancer?

Arsenic

Which heavy metal is most widely stored in the fat?

Mercury

What are chelators

Treatment for metal overdose/reverse toxic effect of heavy metals on enzymes

Pros of chelation

• form nontoxic complexes

• From metals from soft tissues and plasma

• Effective against acute poisoning

• Oral therapy available

Cons of chelation

• redistribution of toxic metal

• Essential metal loss

• No removal of metal from intracellular stores

• Poor clinical recovery

• Pro-oxidant effects (DTPA)

• HA, nausea, increased BP

A young engineer is involved in a smelting accident and presents with rice water stools and severe GI discomfort. Which heavy metal poisoning would you diagnose the patient with?

Arsenic

• Treatment for acute poisoning of arsenic and mercury

• Tx of lead poisoning in junction conjunction with EDTA

• Oily, colorless

Dimercaprol

While dimercaprol is great at chelating arsenic, which chelator is frequently used in its place?

Succimer bc it is water soluble and more stable

• tx of poisoning by antimony

• Water soluble

• Well toldvrated

• Doesn’t delete essential metals in body at usual doses

Succimer

A patient arrives with headaches, fatigue, and loss of appetite with weakened muscles. Which heavy metal do you predict they have been exposed to?

Lead

A small child arrives in the ER ~1 hour after ingesting tablets they had found. Their symptoms included GI distress, vomiting, epigastric pain. Metabolic acidosis and leukocytosis. WHAT DO YOU THINK THE TABLETS CONTAINED?

Iron