Day 9 - Drug, Toxicity, Alcohol, Lead Flashcards
IV vs oral drug - which acts faster? Which drops faster after administration?
IV
-give active form
IV
- comes up fast, declines fast
- oral drops slowly, especially with a slow release
Single compartment vs two compartment model
Single compartment - equal drug distribution in all tissues or only in plasma
Two compartment - distribution differences:
- plasma vs liver
- plasma vs bone
- plasma vs muscle
0 order vs 1st order kinetics
0 order = drug is removed at a constant rate
-independent of concentration and changes to concentration
1st order = rate of drug removal is proportional to concentration
1st drug to treat epilepsy… Current anti-epileptic drugs (3)
Bromide
Phenobarbital
Phenytoin
Primidone
-primidone is a prodrug for phenobarbital
What is the Vd?
Ratio of concentration of drug in the body to concentration of drug in the plasma (ml/kg)
-an imaginary number
A high Vd indicates a high concentration of drug in… A low Vd indicates a high concentration of drug in…
Tissues
Plasma
Equation to calculate 1st order clearance rate
Cf = Ci x 0.5^ (time/half-life)
Ci = dose / Vd
Drug is cleared faster from the body with a high or low GFR?
High
Do ionized or bound drugs go into urine more easily? Are weak acids (aspirin) ionized more at lower or higher pH? Are weak bases ionized more at lower or higher pH
Ionized
Higher
-higher pH = cleared more easily
Lower
-lower pH = cleared more easily
Equation to calculate 0 order clearance rate
Dosing rate = Conc x clearance rate x dosing interval (time)
- rate that drug is lost
- determines how much to replenish
What is the LD50? Is a low or high LD50 more toxic?
Dose that’s lethal in 50% of the population
Low
-very small dose causes death
What is the ED50? Is a low or high ED50 more effective?
Dose that’s effective in 50% of the population
Low
-very small dose can be effective
What is the equation for the therapeutic index? Do we want a high or low TI when determining how safe a drug is?
TI = LD50 / ED50
High
-very high to get to lethal dose, very low to get to effective dose
Which form of a drug can cross the cell membrane - ionized or unionized?
Unionized/uncharged
- via diffusion (absorption)
- lipids in cell membrane block transport of ionized molecules
Blood containing a significant amount of carboxyhemoglobin will appear…
Cherry red color
What’s the best specimen for toxicology testing and why?
Urine since it concentrates metabolites
This is the best analytical method for confirmatory testing for drug abuse and drug toxicity…
Gas chromatography/Mass spec
- sample is vaporized and injected onto chromatographic column for GC
- MS fragments vaporized molecules into charged molecules
- separation into mass and charge
Almost 90% of all human drugs are metabolized by this enzyme…
CYP (CYP450 screening)
Drugs screened for in urine (8)
Amphetamines Barbiturates Benzodiazepines THC BE (cocaine) Opiates (morphine) PCP Propoxyphene
What is the drug schedule based on? How many schedules are there? Which is the most restricted?
Potential for addiction
5
Schedule I
Adulterants in drug testing can be detected by using reagent test strips that test for (4)…
Nitrate
Glutaraldehyde
Creatinine
-tampered sample has very high creatinine
pH
Drawback of using immunoassay for drug testing
Cross-reactivity
-different analyzers will have different cross-reactivity
Difference between gas chromatography and HPLC
GC uses gas phase
HPLC uses liquid phase
- solid phase and mobile phase
- analytes with greater affinity for stationary phase elute later than those with greater affinity for mobile phase
GC and HPLC separate compounds based on (3)
Size
Polarity
Reactivity
- HPLC - need to know what to look for, more interference
- Mass spectrometry - don’t need to know, less interference
The primary product of ethanol metabolism that is toxic is… The process uses this enzyme…
Acetaldehyde
ADH (alcohol dehydrogenase)
Too much alcohol triggers an imbalance in this molecule…
NADH/NAD+
- too much NADH buildup
- interferes with glycolysis
What process is alcohol interfering with in fetuses?
Vitamin A
Alcohol will cause the osmolar gap to be…
> 10 (elevated)
The chemical in antifreeze is… These crystals form in the urine in patients with antifreeze toxicity…
Ethylene glycol
Calcium oxalate crystals
-found in normal urine
How do we treat lead poisoning?
Chelating therapy
- add something to bind to heavy metal so it can be removed from the body
- nonspecific
- patient can develop deficiency in other trace metals
- chelaters: EDTA, DMSA
Lead poisoning is detected by testing this specimen… What is the lead testing called and how is it performed?
Blood
Anodic stripping voltammetry
- lead inside RBCs will leech out into reagent
- add electrode and run current to determine amount of lead that leaked out
- uses gas chromatography for confirmation (no need for GCMS)
Lead poisoning affects this body system…
CNS
In the body, lead is deposited into (2)…
RBCs
-inhibits hemoglobin synthesis
Bone
-stays for decades, slowly releasing into circulation
A person with lead poisoning will show a blood smear with RBCs showing… What does lead do inside RBCs?
Basophilic stippling
Inhibits hemoglobin synthesis by inhibiting ALA
- rate limiting step in heme synthesis
- severe anemia results
Lead causes this hemoglobin protein to build up in the blood and urine
ALA
What does lead do in the kidneys? How does lead cause gout?
Inhibits ion transport and excretion
Inhibits uric acid excretion
-uric acid buildup causes gout
Lead exposure - routes of entry (2)
Inhalation (organic lead gasoline)
Food/ingestion
For therapeutic drug monitoring, when do drugs peak for an IV dose? Oral dose?
10 mins
1 hr
-trough = just before next oral or IV dose
Aminoglycosides, gentamicin, amikacin, tobramycin, vancomycin are examples of this group of drugs…
Antibiotics
Digoxin (Lanoxin), procainamide (Pronestyl), lidocaine (Xylocaine) are used to treat…
Heart/cardiac
Acetaminophen (Tylenol) and aspirin are…
Analgesics (painkillers)
Cyclosporin (Sandimmune) is used as an…
Immunosuppressant
- used for transplant patients
- inhibits IL-2
- stops lymphocyte proliferation
Lithium (Eskalith) is used to treat…
Bipolar depressive disorders
Overdose on aspirin can cause… Overdose on acetaminophen (Tylenol) can cause…
Bleeding
-interferes with platelet aggregation
Hepatic necrosis, liver failure
-drug is metabolized in the liver to glucuronide and metabolites
Bound vs free drug - which is active and which is inactive?
Bound = inactive
Free = active
Biotransformation of a drug is when a ___ is metabolized into a ___. Which is hydrophobic and which is hydrophilic?
Parent compound = hydrophobic
Drug metabolite = hydrophilic
-can be eliminated in body through blood, bile, urine
Are parent compounds more or less active than their metabolites? The exceptions are called…
More active
- metabolites less active
- this is usually the case
Prodrug
-metabolites more active
What are the 4 outcomes once a parent compound is converted into a drug metabolite?
Active metabolite
Inactive metabolite
Toxic metabolite
No change (from parent compound)
The clearance rate of aspirin is affected by…
Blood pH
- aspirin is a weak acid
- can be ionized and cleared faster at higher pH
What is the urine clearance time for 1 joint of THC? The test can be adulterated by degrading THC with…
5 days
Bleach
-also Visine, Urinaid, Joy Soap
How is ethylene glycol poisoning treated?
Give ethanol to compete with ADH (alcohol dehydrogenase)
-alternative: fomepizole at 10 mg/kg for 3 doses total (expensive)
What is ethanol’s metabolic effect on: lipogenesis, ketone bodies, glycolysis
Increase
Increase
Decrease
Upon a breathalyzer test, there must be a waiting period of ___ and there must be a time of ___ since the last rinsing of the mouth
15 minutes since last drink of alcohol
6-7 minutes
Ethylene glycol lab results: pH, pCO2/CO2, osmolality, anion gap
Low
Low
High
High
In a mass spectrometry reading, what are the smaller peaks after a large spike?
Isotopes
-C13 atoms in atmosphere give +1 to molecular weight
A mass spectrometry quantifies based on… There is a tradeoff between these two things…
Mass to charge ratio upon ionization
Resolution and signal
- high resolution = low signal
- high signal = low resolution
