pharm 141 - toxicology

Toxicology is the study of

adverse effects

What is the difference between toxins and toxicants?

toxins are natural, toxicants are synthetic

Toxins can be classified by (3)

source, location, use

With repeated dosing, a drug with a ____ ½ life is dangerous since it can accumulate in the body and cause toxic effects

long

T/F dose response curves can be made for adverse effects

T

Max effect or Emax is _____% of the effect you are measuring where the dose-response curve ______

100, plateau

T/F a max effect is always therapeutic effect

F, can be toxic

The _____ is the concentration at which 50% of the max effect is observed

EC50

The _____ is the concentration at which 50% of toxic max effect is observed

TC50

The ____ is the dose at which 50% max therapeutic effects OR 50% subjects experience particular therapeutic effect

ED50

The ___ is the dose at which 50% of max toxic effect is observed OR 50% subjects experience particular toxic effect

TD50

The ___ is the dose at which 50% subjects experience mortality due to drug

LD50

_____ is a drug that has a narrow therapeutic concentration which is why dosing and monitoring is very important

digoxin

The therapeutic index (TI) is the ratio of ___ to ___

TD50, ED50

To find effective dosing, you can use ratio of ___ to ___

LD50, ED50

T/F you can have multiple therapeutic windows for a single drug

T

Are ED50, TD50, and LD50 at an individual or population level?

population

The margin of safety window is the ratio of _____ to ______

LD1, LD99

Should drugs with small margin of safety be closely monitored?

yes

A dose response curve for an essential substance (vit, trace element) typically follows ___ shape

v

For an essential substance, you want to be in the _______________ where the dose is neither deficient or toxic

region of homeostasis

Beyond the region of homeostasis what happens?

toxicity or deficiency

In a dose response curve, the effects start as ______ then at higher [ ] they may become _______

protective, toxic

What is NOAEL AKA threshold dose

no observed adverse effect level

What is LOAEL

lowest observed adverse effect level

Compare NOAEL and LOAEL:

You see adverse effects at _____ and none at _____

LOAEL, NOAEL

T/F no adverse effects are observed at LOAEL

F

Almost all adverse effects are ____ related

dose

What are examples of non-dose related adverse effects?

allergy, serotonin syndrome

______ ______ are immune system mediated and occur to previously sensitized substance

allergic rxn

______ ______ are unexpected unexplained reactions sometimes caused by genetic differences

idiosyncratic rxn

How can you avoid dose-related adverse effects?

reduce or adjust dose

How can you avoid non-dose related adverse effects?

avoid drug

What is the extension effect?

adverse effect is extension of primary effect of drug

For the extension effect, the primary effect and adverse effect have ______ mechanism of action

same

An example of extension effect is using benzodiazepine for anxiety. However, as you increase the dose what can occur?

sedation and coma

An example of extension effect is a1 antagonists for hypertension. However, as you increase the dose, ______ ______ can occur

orthostatic hypotension

For off target effects, the primary effect and adverse effect have ____ mechanism of action

different

An example of off target effects is promethazine which is a gen 1 antihistamine that can block histamine receptors and cause ______. It is also _____ adrenergic receptor antagonist that causes orthostatic hypotension

sedation, a1

T/F reversibility is a way to classify adverse effects

T

An example of reversibility is ethanol ingestion that causes liver inflammation. At low doses, it is ______ but prolonged use can result in ______ _________ such as cirrhosis

reversible, organ remodeling

With high dose prolonged ethanol ingestion, cirrhosis can occur. Will it reverse once ingestion stops?

no

T/F Most adverse effects occur during drug exposure but some can occur later when the drug is no longer in the body

T

An example of delayed effect is DES which was used to prevent _______ but increased the risk of _______ ________ in female offspring

miscarriage, vaginal cancer

Older chemotherapy drugs for cancer caused damage to multiple tissue types. Would these drugs be classified as organ specific?

no

T/F most drugs have antidotes that can reverse their effects

F

Acetaminophen is metabolized by ____ pathways, __ of which produce non-toxic metabolites

3, 2

The third pathway of acetaminophen metabolism produces toxic metabolites via P450 enzymes _____ and _____

CYP2E1, CYP3A4

T/F at high doses of acetaminophen, its toxic metabolites can cause dysfunction and cell death

T

At low doses of acetaminophen, what molecule can neutralize the toxic metabolite?

glutathione

What are signs of acetaminophen poisoning?

acute nausea and vomiting, improvement before liver failure

How is acetaminophen poisoning treated?

IV N-acetylcysteine within 8h

N-acetylcysteine reverses acetaminophen poisoning by augmenting ______ reserves

glutathione

Ethanol is rapidly absorbed in the GI tract. How can you slow it down?

food

Food in the stomach can delay _____ ______ which delays passage of alcohol to small intestines where it is absorbed

gastric emptying

What enzyme metabolizes ethanol in the GI tract and liver?

aldehyde dehydrogenase (ADH)

There are 2 metabolic steps in alcohol detoxification that uses _____ enzyme and requires _____

ADH, NAD+

What is the rate limiting step of alcohol metabolism?

NAD+

T/F alcohol metabolism is saturated at high concentration

F, low

Most alcohol is metabolized into _____ and the remainder is excreted (urine, sweat, lungs)

acetate

Alcohol metabolism begins with _____ converted to acetaldehyde by ______ _______ then converted to acetic acid by _______ ________

ethanol, alcohol dehydrogenase, aldehyde dehydrogenase

Individuals with alcohol use disorder use this enzyme to metabolize alcohol which contributes to hepatotoxocity

CYP2E1

Excess production of aldehyde can occur via 2 polymorphisms; _____ _____ and _____ ______

fast ALD2 2, slow ALDH2 2

Individuals with the fast polymorphism (ALD2*2) convert alcohol to aldehyde ______ via _______ _______

rapidly, alcohol dehydrogenase

Individuals with the slow polymorphism (ALDH2*2) convert acetaldehyde to acetate _____ via ________ _______

slowly, aldehyde dehydrogenase

Metabolism of _____ to toxic formaldehyde and formic acid can cause blindness, metabolic acidosis, death

methanol

What drug can be used to inhibit alcohol dehydrogenase?

fomepizole

To prevent methanol metabolism into toxic ints, what molecule can be used?

ethanol

T/F ethanol and methanol compete for alcohol dehydrogenase

T

What drug can be used to inhibit aldehyde dehydrogenase?

disulfiram

Initially, ethanol causes reversible liver damage. Overtime, fat accumulates due to excess ______ (by product of ethanol metabolism) and can lead to _______

NADH, fibrosis

T/F chronic inflammation due to ethanol consumption can cause fibrosis which allows the liver to regenerate

F, prevent regeneration

Neurons are dependent on _____ metabolism which is why tissue is sensitive to ____ or _____ deprivation

aerobic, O2, glucose

The ____ exists to protect the brain since it is very sensitive to changes

BBB

______ is a drug that caused rapid Parkinson’s disease in 20 year olds but was later found to be MPTP

meperidine

MPTP is converted to ____ via MAO-B where it inhibits ______ ________ resulting in neuron death

MPP+, oxidative phosphorylation

_____ is a herbicide and MPTP like environmental toxin that is used to induce Parkinson’s in models for studying

rotenone