LMP301 Lecture 17: Toxicology Flashcards
define: mithridatism
taking poisons in small doses to develop tolerance
define: xenobiotics
pharmacologically active substance that is not produced in the body(e.g. drugs)
TDM
therapeutic drug monitoring
The difference between toxin and anecdote is…
dose
define: pharmacodynamics
how the drug affects your body
define: pharmacokinetics
what the body does to the drug
difference between pharmacodynamics and pharmacokinetics
what the drug does to the body vs. what the body does to the drug
absorption, distribution, metabolism of the drug is pharmacodynamics / pharmacokinetics?
pharmacokinetics
drug-receptor interaction is pharmacodynamics / pharmacokinetics?
pharmacodynamics
difference between toxicology & TDM
toxicology: harmful substance
TDM: medicine
define: biotransformation
converting fat soluble chemicals to hydrophilic chemicals to be excreted in the urine/bile
biotransformation alters the biological properties of xenobiotics so…
it become less toxic (detoxification)
what makes xenobiotics less toxic?
biotransformation
what happens in rare cases when biotransformation on xenobiotics don’t react as expected?
makes a more toxic metabolite (e.g. metabolism of alcohol)
enzymes that carry out biotransformation can be put into 4 categories… (main reactions that happen)
- hydrolysis
- reduction
- oxidation
- conjugation
examples of conjugation reactions
- glucuronidation (add glucuronic acid / B-glucuronide)
- sulfonation (add sulfate)
- add glycine
- add glutathione
define: glucuronidation
addition of glucuronic acid to a substrate
enzymes involved in biotransformation are usually ____, so activity differs among individuals
polymorphic
what limits exposure of orally ingested xenobiotics?
small intestines & liver
Phase I of toxin metabolism
- activation/inactivation of compounds
- change pharmacological activity (make drug less toxic)
where does most of the phase I activities take place?
liver mitochondria
which enzyme is involved in phase I?
cytochrome P-450 system
- oxidation
- reduction
- hydrolysis
how are drugs processed by the P450 class of enzymes? (slide 8)
- attached to P450-Fe3+
- Fe3+ gets reduced to Fe2+ (attached to P450-Fe2+)
- O2 is added = peroxide dianion
- 2H+ is added, which removes oxidized drug + water from P450-Fe3+
- P450-Fe3+ goes on to attach to more drugs
what reduces Fe3+ to Fe2+ in the P450 enzyme system?
reduced P450 reductase
reduced [P450 reductase] + [Fe3+] -> [P450 reductase] + [Fe2+]
what changes oxidized flavoprotein -> reduced flavoprotein?
NADPH
[NADPH] + [P450 reductase] -> [NADP+] + reduced [P450 reductase]
What element does the drug bind to on P450?
N
binding of the drug to P450 changes…
conformation of the enzyme, and exposes drug to other reactions
the active form of the drug is oxidated / reduced?
oxidated
Which is the oxidated state: Fe3+ or Fe2+?
Fe3+
steps of drug metabolism
- activation / inactivation
- conjugation products
- elimination
what is phase 2 of the drug metabolism pathway?
conjugation reactions
where does phase 2 normally happen?
liver & kidneys
purpose of conjugation
enhance excretion of drugs; facilitate excretion
function of B-Glucuronidase
a-glucuronic acid -> B-glucouronide
what catalyzes the reaction a-glucuronic acid -> B-glucouronide
B-Glucuronidase
what transfers B-glucuronide to drugs?
UDP glucuronosyl transferase
what is attached to drugs to make it more soluble?
B-glucuronide
besides drugs like morphine, what else is glucuronidated?
bilirubin
most important route of drug elimination is…
why?
kidneys
- glomerular filtration
- active tubular secretion
less common drug excretion pathways
- drug into bile (happens in intestine)
- breath
- breast milk
- saliva
why do we build up good drug tolerance if we continuously take small doses?
prime the elimination pathways to be very good at getting rid of toxin (esp. the less common elimination paths)
normal metabolism of alcohol
ethanol -[ADH]-> acetaldehyde -[AcDH]-> acetate
acetate goes to TCA
where does alcohol metabolism take place?
- cytosol (ethanol -> acetaldehyde)
2. mitochondria (acetaldehyde -> acetate)
ADH
alcohol dehydrogenase
AcDH
acetaldehyde dehydrogenase
what is different when there is abnormal alcohol metabolism
- not enough NAD+ to work with AcDH, so there is build up of acetaldehyde
- not enough NAD+ to work with TCA, so build up of acetyl-CoA
- pyruvate gets converted to lactate instead because it can’t enter TCA (metabolic acidosis)
- no TCA = fatty acid metabolism favoured = fatty deposits in the liver
what is the toxic metabolite of alcohol metabolism?
acetaldehyde
what allows acetate to be used in the citric acid cycle?
Acetate + CoA = acetyl-CoA
why will alcoholism lead to fatty liver?
build up of acetyl CoA in the liver stops liver cells from getting enough ATP through aerobic respiration.
fatty acid metabolism causes fatty deposits in liver.
what is needed to convert pyruvate -> lactate?
NADH
what contributes to hangover effects?
- metabolic acidosis from lactic acid
- acetaldehyde build up
effect of acetaldehyde build up
- damage / immunological response
2. necro-inflammation / apoptosis of hepatocytes
what liver enzyme can be seen abnormally when there is acetaldehyde build up?
ALT
effect of chronic alcohol ingestion on intestines (and effects that may have)
- increase permeability of intestines
- endotoxin release
- Kupffer cells take up endotoxins
- release cytokines
- cytokines activate stellate cells & cause hepatocyte apoptosis
- stellate cells secrete matrix proteins, which makes liver harder
define: endotoxins
toxin that is present inside a bacterial cell and is released when the cell dies
Another name of Ecstasy
MDMA
define: diaphoretic
sweating a lot
which race has the most toxic MDMA metabolite?
south(east) Asian girls
MDMA is a derivative of…
methamphetamine
metabolite of MDMA
MDA
is the metabolite of MDMA active?
yes
are MDMA & MDA products that can be found in the body naturally?
no, synthetic
absorption & metabolism of MDMA
absorbed: intestines
metabolized: liver
physical effects of MDMA
- more awake
- higher energy, endurance
- less fatigue
psychological effects of MDMA
- euphoria
- sharp sensory perception
- more social
- feel closer to others
MDMA activation
MDMA -> MDA -> HHA
MDMA -> HHMA
what is produced at the end of MDMA phase I?
- HHA
- HHMA
MDMA conjugation
- HHA & HHMA can be conjugated (glucuronide / sulfate) & excreted in urine
- HHA & HHMA can be further metabolized
- metabolites conjugated with glutathione & excreted in urine
what enzyme conjugates glutathione?
GST (Glutathione S-transferase)
what is needed to conjugate MDMA metabolites?
nothing!
GST helps speed up process, but it is not necessary
secretion of MDMA?
in urine after conjugation
why do MDMA and tylenol not go well together?
MDMA metabolism uses glutathione for conjugation, and so does tylenol metabolism. Activated form of tylenol (NAPQI) is very toxic, but can’t be excreted if it can’t conjugate with glutathione.
what complex is formed during glutathione conjugation?
Mesenheimer complex
effect of decreased glutathione stores
- influx of Ca into cell
- changes in cell membrane
- hepatocyte necrosis
MDMA will initiate a(n) ___ response, which will cause…
immune
inflammation
the negative effects of MDMA metabolism will cause…
VERY HIGH fever
