Unit 1 Flashcards
Define Therapeutic Window.
The difference in plasma concentration [Cp] between the desired and adverse
response MEC
Define Steady State
When the rate of drug administration [RATE IN] equals the rate of drug elimination [RATE OUT]
Pharmacodynamics
What the drug does to the body
Define Bioavailability
The fraction of unchanged drug reaching the systemic circulation following administration by
any route.
AKA transfer of drug from site of adminstration –> blood
What is volume distribution?
The drug dose needed for desired plasma concentration
Define distribution
movement of drug from blood stream into tissue
What is the major organism for metabolism?
The liver
What is the major organism for excretion?
The kidney
Four factors influencing drug membrane passage
- Molecular size - can be affected by drug binding to plasma proteins
- Lipid solubility - estimated by oil:water partition coefficient
- Degree of ionization - affected by tissue pH, will influence lipid solubility
- Concentration gradient - created at site of administration
What size molecules can diffuse through aqueous channels?
100-200 MW
What is the major method of diffusion for drugs with molecular weight 500-800?
lipid diffusion
Formula for bioavailability?
Area under the curve (AUC) via any route (usually oral)
______________________________________
Area under the curve intravenous
What is another term for bioavailability?
Extent of absorption
Two main factors that dictate the plasma concentration?
- Rate (time to peak)
2. Extent (Bioavailability)
What is first pass effect?
When the drug concentration is greatly reduced due to liver metabolism or gastric metabolism
Define rate of absorption
the peak concentration plasma or the time to attain peak plasma concentration
Enteric coating
fatty acids applied to oral medication to protect medication from the stomach.
protects drug from the stomach acidity and can only be broken down in the small intestines (more basic environment)
parenteral route
any drug that is NOT administered via the gastrointestinal tract
A generic drug formulation is said to be bioequivalent to a brand name drug formulation if:
- Rate (estimated by maximum of peak drug concentration [Cmax]) and extent (bioavailability) that the active ingredient drug is absorbed and becomes available at the site of action (drug entering systemic circulation) is similar (within set limits) to the brand name product
- Drugs are considered bioequivalent if the 90% confidence interval of the mean AUC and
the mean Cmax of the generic product (T-test) is within 80-125% of the brand product
What are two main things to considered when choosing drug route adminstration?
bioavailability and relative rate of onset
Example of enteral routes of administration?
Oral and rectal
Is the rate of absorption higher in the stomach or the small intestines?
Small intestines because it has larger surface area!
Benefits of using IV drugs?
most accurate and rapid onset (
How would you administer a drug that has a limited therapeutic window?
Use an IV
Cons of using IV
bypasses absorption barriers and can introduce infectious agents
easy to reach toxic levels very quickly
Bioavailability of intramuscular injection?
100%
What is a depot intramuscular injection?
an intramuscular injection of a drug in an oil suspension that results in a gradual release of the medication over several days.
When to use intramuscular injection?
What drug is too irritating for subcutaneous injection
Why wouldn’t you use intramuscular injection?
absorption can be erratic
pain
tissue necrosis (if high pH)
microbial contamination
When to use a subcutaneous drug?
For slower, constant rate absorption
period of drug absorption can be altered intentionally
How would you adminster a non-irritating drug?
subcutaneously
When would you administer a drug via inhalation?
For rapid onset of systemic drug effects (general anesthetics, nicotine, “crack” cocaine,
marijuana)
Why are inhaled drugs absorbed so quickly?
Due to large surface area and high blood flow in pulmonary tissue
What is a transdermal drug?
Application of patch to skin for treatment of systemic conditions (e.g., hypertension, angina, pain, hormonal
replacement therapy, smoking cessation)
Benefit of using a transdermal drug?
Bypasses the first pass effect
Cons of transdermal drug?
Prolonged drug levels can be achieved - potential for unexpected drug accumulation and toxicity
What are two things to look for if an anemic patient has an appropriate reticulocyte response?
Hemolysis and hemorrhaging
ideal particle size for local inhalation?
1-5 micromolarity has therapeutic effect
what are some risks associated with local inhalation of aerosolized particles?
Irritant drug may induce bronchospasm (aerosolized liquid/solid particles remain in suspension)
What are some risks associated with local topical drugs?
Generally minimal systemic absorption, but can be significant under some conditions, e.g., application over
large area, to denuded area, use of occlusive dressings, or with highly lipid soluble drugs.
Is rectal drug onset rapid or not rapid?
onset is not rapid
How does the bioavailability for rectal drugs compare to oral drugs?
bioavailability for rectal drugs are generally greater than oral administration
compare the first pass metabolism between rectal and oral drugs
First pass metabolism for the rectal route is less than for the oral route. 50% of rectal drugs bypass the liver
Describe the onset and bioavailability for Sublingual - Buccal drug
onset is within minutes and bioavailability generally high
Describe Sublingual - Buccal drugs ability to bypass the liver
After absorption from oral mucosa, venous drainage from mouth is to the superior vena cava, protecting the drug
from rapid hepatic first pass metabolism plus faster onset of action
How would you administer a drug that is needed for rapid systemic onset?
inhalation
How would you administer a drug needed to treat a systemic CONDITION?
transdermal patch to treat hypertension, angina, pain, hormonal replacement therapy, smoking cessation - 1st pass metabolism is avoided
Name four important tissues with tight junctions between cells
- GI mucosa
- Blood-brain barrier
- Placental
- Renal tubes
How do you tell the difference between the dissociation of a proton of an acid vs base?
dissociation of a proton from an acid produces an ionized drug (COO-), whereas dissociation of a proton from a base produces an unionized drug (NH2)
Are nonionized or ionized drugs more readily absorbed?
non-ionized
Define pka
refers to the pH of a solution at which the concentrations of the protonated and nonprotonated
forms of the drug are equal (and is a constant for any given drug)
At what pH are weak acids ionized?
alkaline solutions
ph > pka
Is the deprotonated form of an acid ionized or unionized?
ionized COO-
Is the deprotonated form of a based ionized or unionized?
unionized B
At what pH are weak acids unionized?
acidic solutions
pH
At equilibrium, the unionized concentration on both sides of the membrane is..
equal
At equilibrium, where is the total concentration of drug greatest?
The side where ionization is greatest because drugs are trapped where they are predominantly ionized
What type of solution traps acidic drugs?
basic solutions
What type of solution traps basic drugs?
acidic solutions
What type of pores can ionized drug molecules pass through?
capillary wall pores
What protein do acidic drugs primarily bind to?
albumin
What protein do basic drugs primarily bind to?
alpha-1 acid glycoprotein
Define Volume of Distribution
Size of compartment necessary to account for total amount of drug in the body if it were present
throughout body at same concentration found in plasma.
gives an indication of the extent to which a drug
passes from plasma to extravascular tissue
Formula for the volume of distribution
Vd = amount of drug in body (Ab) /
concentration of drug in plasma (C0)
What is a higher volume of distribution indicative of?
indicative of drugs located mostly outside plasma (increased tissue binding, high lipid solubility)
What is a lower volume of distribution indicative of?
Lower values are generally indicative of drugs located mostly inside plasma or ECF (extensive binding to plasma proteins, large size, or low lipid solubility)
What is the bioavailability for intravenous drugs?
100% since all the dose is placed in the blood
What drugs fall within 75-100% availability, approaching 100%?
intramusculuar, subcutaneous, sublingual-buccal, inhalation, transdermal
because tissue environment is non-destructive for most drugs
What drug has the most variability when it comes to bioavailability?
oral.. can be anywhere from 0-100% due to passage through the GI tract or 1st pass effect metabolic effect
What is the most rapid onset drug?
inhalation and intravenous
Which one probably has a faster onset: inhalation or intravenous drugs?
inhalation drugs getting to the central nervous system
Which drug route is potentially more dangerous: inhalation or intravenous?
intravenous because you can put an unlimited number of molecules in the plasma compartment
Name drugs that have an intermediate speed of onset
sublingual-buccal, intramuscular, subcutaneous
Name drugs that have a slower speed of onset 15-30 min
oral- intermediate release formulations
Name drugs that have the slowest speed of onset (hours)
Transdermal and oral - enteric coated and sustained release formulas
intramuscular and subcutaneous also have depot forms
An increase in gastric motility generally has what effect on the rate of oral absorption?
increases the rate of oral absorption
An increase in gastric motility has what effect on the extent of bioavailability?
no change in the extent of bioavailability
Is transdermal route of administration for local or systemic effects?
Treatment of SYSTEMIC CONDITIONS
What are the four factors influencing drug distribution?
- Special anatomic barriers - tight junctions
- pH of biologic fluids
- Lipid solubility of non-ionized drugs
- Drug binding to plasma protein
True or False: Drugs can cross the blood-brain barrier through specific transporters?
TRUE
What type of drugs can readily cross the blood-brain barrier?
Lipid soluble drugs
When will a weak acid most readily cross membranes?
When it is contained in acidic fluids!
so long as there is an unionized form of drug, what site will the drug be best absorbed?
always the intestines!
surface area always trumps percent unionized as long as there is an unionized form
How to treat aspirin overdose?
Alkalize the urine with sodium bicarbonate so the aspirin (weak acid) gets trapped into the basic solution for excretion
What effect does protein binding have on drug half life?
Increases it
another way to describe small volume of distribution?
most of the drug hangs out in the plasma
How to avoid bolus toxicity while giving a drug via IV?
administer via slow IV push
“Bolus” or “slug” effects are most likely to be seen when drugs are administered by which of the following routes?
intravenous
Explain what C0 is..
extrapolation to time zero gives C0, the hypothetical drug concentration predicted if the distribution had been achieved instantly.
Must connect the line linearly to give time for the drug to distribute! If you take the highest concentration plotted on the graph, you haven’t allowed enough time for the drug to distribute throughout the body.
Drugs highly bound to plasma proteins?
Heparin (4L)
Warfarin (10L)
Drugs that freely enter cells (small molecules)
Lithium (46L)
Ethanol (42L)
Drugs highly water soluble that don’t enter cells?
Ibuprofen (11L)
Gentamicin (22L)
What is the expected volume of distribution for a drug that is highly bound to plasma proteins
3-5 Liters
How does the alcohol concenctration differ in someone who is obese?
An obese person has a higher fat %, lower volume of distribution of alcohol (need aqueous solution), and alcohol percentage INCREASES
aka fat people get drunk faster
What is the primary organ for drug metabolism?
The liver
What is the most frequent pathway for drug metabolism?
oxidation
What is phase I in biotransformation?
An enzyme exposes a polar group on the lipophilic molecule [-OH, -NH2, -SH]
What are phase I reactions?
Oxidation, reduction, and hydrolysis
What is phase II in biotransformation?
Conjugation.
Endogenous substrate links up with the polar functional group from phase I and a HIGHLY polar conjugate that can be readily excreted through the urine
What is the pka of the conjugate in phase II
lower than the drug so that the drug is IONIZED at most physiological pH and also makes it larger
Relevance of CYP2D6 enzyme?
It’s needed to convert codeine into morphine (more active drug)
What is the most common outcome of drug metabolism (>95%)?
Inactivating-detoxifying process that forms readily excreted and pharmacologically inactive metaabolites
An example of an inactive prodrug?
Valacyclovir
Example of a drug that can be broken down to a toxic metabolite?
Acetominophen (tylenol)
Drug metabolism usually results in what type of products?
One that is less likely to distribute intracellularly and is more water soluble than the parent drug
What is the main reaction type for phase I metabolism?
oxidation
What is the main reaction type for phase II metabolism?
conjugation
What is the main enzyme for phase I metabolism?
CYP450
What is the main enzyme type for phase II metabolism?
transferases
Which metabolic phase is significantly impacted by genetic polymorphisms?
BOTH
Which metabolic phase changes with age?
phase I - decrease 1/3. So, if you have the option to administer a phase I or II drug, use phase II for a 75-year-old
Which metabolic phase is more saturable?
phase II because you have a limited supply endogenous biochemical unit (highly reactive) to conjugate with drug
Important reactions in phase II metabolism
Glucuronidation, acetylation, glutathione / glycine / sulfate conjugation
most common detoxifying agent in phase II metabolism
glutathione is the detoxifying agent for acetaminophen
are most drugs first order or zero order kinetics?
95% of the drugs in use at therapeutic concentrations are eliminated by first order elimination kinetics.
the rate of elimination is proportional to the drug concentration. This means that the higher the drug concentration, the higher its elimination rate.
describe zero order kinetics
same amount of drug eliminated no matter what the drug concentration is.
Process is SATURATED!
Where is the most abundant supply of cyt450 found?
Liver smooth endoplasmic reticulum
Name the cofactors and enzymes involved in phase I metabolism
NADPH
flavoprotein NADPH-cytochrome P450 reductase
molecular O2
Which phase has postnatal variability?
Phase I - Cyt450
Name characteristics of drugs metabolized by cyt450
- Lipid soluble
- requires molecular O2
- Usually become more highly oxidized
- Metabolised in the smooth endoplasmic reticulum
Why is saturability minimal in phase I metabolism?
You’re not likely to run out of NADPH or molecular O2
CYP3A4
major drug metabolizer found in gastric mucosa not in large intestines (won’t be metabolized the rectal route)
CYP2E1
The enzyme that can turn acetaminophen into a toxic metabolite in liver
CYP2D6
codeine –> morphine
opioids
antidepressants/antipsychotics
tons of genetic polymorphisms here
CYP2C9
metabolizes warfarin
What is warfarin?
anticoagulant / blood thinner
What are the detoxifying effects of CYP2D6 enzyme?
metabolizes antidepressant medication
Detoxifying Clinical effects of a poor metabolizer CYP2D6?
increased antipsychotic toxicity
Detoxifying Clinical effects of a ultra metabolizer CYP2D6?
nonresponse to antidepressants reported
What are the activating effects of CYP2D6 enzyme?
activates codeine –> morphine
What are the activating clinical effects of a poor metabolizer CYP2D6?
insufficient analgesia with codeine due to failure to metabolize to active metabolite morphine
What are the activating clinical effects of a ultra metabolizer CYP2D6?
codeine intoxication due to rapid metabolism to morphine
CYP2C19
acts on proton pump inhibitors (PPI)
What are the two genetic polymorphisms detected by the Amplichip® CYP450 Test?
CYP2D6 and CYP2C19
What enzyme does warfarin target?
vitamin k reductase (VKORC1) which is needed for coagulation. Warfarin inhibits this enzyme
dealkylation is what type of reaction?
oxidation
Name an important enzyme for neurotransmitter metabolism
monoamine oxidase
Name the phase I reductions (rare)
azo reduction
nitro reduction
carbonyl reduction
What type of reeduction can produce toxic intermediates?
nitro reduction
Name two types of molecules hydrolyzed in phase I (rare)
esters and amides
Esterases are commonly used to make what type of drug?
pro drugs ex: valcyclovir
If you give acetaminophin to a 3 year old, what is the most likely enzyme pathway?
sulfer transferase. The glucuronyl transferase is not developed until 3-4 years of age.
Which pathway is important for the detoxification of carcinogen, pollutants, and toxic metabolites?
Glutathione conjugation
Local anesthetics are…
amidases and estherases
How do you know if a local anesthetic is an amide or esther?
If there is an extra “I” in the prefix it is and am”I”de
What is the main mechanism of CYP450 inductions?
Increased synthesis of enzyme protein
How long does drug induction take?
Generally requires 48-72 hrs to see onset of effect
How long does drug inhibition take?
can occur as soon as sufficient hepatic concentration is reached (generally within hours)
What is the role of P-Glycoproteins?
Transporters located on membranes of intestinal, renal and hepatic epithelial cells that play a role in
elimination of xenobiotics, including drugs.
decrease absorption and enhances elimination
Inhibitors of p-glycoproteins will..
increase plasma levels of drug substrates
Inducers of p-glycoproteins will…
decrease plasma levels of drug substrates
Name the clinically Relevant Inducers?
- Phenobarbital
- Phenytoin
- Carbamazepine
- Rifampin
- Ethanol
- St. John’s Wort
- Tobacco smoke (not nicotine)
Name the clinically relevant inhibitors
- Cimetidine
- Erythromycin / Clarithromycin
- Ketoconazole / Azole antifungals
- Fluoxetine (and other SSRIs
- Grapefruit juice
- HIV protease inhibitors
- Omeprazole
What is the most important organ for secretion?
The kidney
What type of drugs can be reabsored?
ones that can go through membranes: lipids, unionized
What is the Glomerular Filtration rate?
120 ml/min
How are stronger acids and bases in the proximal tubule secreted?
via Active Tubular Secretion at rate of 120-600 ml/min.
drugs that are lipid-soluble and uncharged are cleared at what rate? Why?
only 1 ml/min because of tubular reabsorption
What’s the one way you can affect glomerular filtration rate?
altering drug-protein binding (very difficult to do)
What is Enterohepatic Cycle?
the reabsorption of drugs from the intestines back to the liver by way of the superior mesenteric and portal veins. This process reduces the elimination of drug and prolongs its half-life and duration of action in the body.
What is the significance of beta-glucuronidase and estrogen?
beta-glucuronidase produced by bacterial enzymes hydrolyzes the conjugate back to its free drug state so that it can be reabsorbed
How does an antibiotic affect beta-glucuronidase?
It stops the production of the bacterial enzyme beta-glucuronidase which is needed for the enterohepatic reabsorption of estrogen.
Estrogen levels go down. Birth control don’t work. Unplanned pregnancy
The addition of glucuronic acid to a drug molecule:
increases its water solubility and usually leads to the inactivation of the drug
n-acetylation takes place during what phase of metabolism?
phase I
What is the product of n-acetylation?
Acetyl group is donated by acetyl CoA
NOTE: Some products are less water soluble (certain sulfonamides)
What are the two most important termination mechanisms?
Hepatic metabolism and renal excretion
What is ke, the rate constant of elimination for a drug?
The fraction of drug leaving body per unit time via all elimination processes.
What is the half life formula?
t1/2 = .693 / Ke
What is the formula for clearance?
CL = Vd x ke
gives the fraction of the volume of distribution that is completely cleared of drug per unit time.
Key points about first order kinetics?
The half life remains the same no matter what! Think of the slope
The rate of elimination varies with the plasma concentration
How many half lives does it take to get rid of a drug?
4-5
How many half lives does it take to reach steady state?
4-5
What two variables is half life dependent on?
clearance and volume of distribution
If clearance goes up, the half life goes..
down.. its being cleared out faster!
If volume of distribution goes up, half life goes..
UP
high volume of distribution means you have less drug in the plasma. Less plasma concentration (less ability for it to be eliminated) thus GREATER half life
Is clearance and volume of distribution dependent on one another?
No, both variables are independent of each other.
CL = Vd * Ke
you can change the clearance of a drug and NOT the volume of distribution
What variables do you need to calculate the loading dose?
the volume of distribution and the desired plasma concentration.
You don’t need the half life at all!
What type of clearance is subject to co-administration of inducers and inhibitors?
Hepatic Clearance
What type of extraction drug is highly dependent on blood flow?
HIGH extraction drugs. (going through liver and most of the drug is chewed up and extracted thus dependent on blood flow to the liver).
Hence, why phase I metabolism decreases with age.. less blood flow!
If you give an inducer when will you see faster clearance (via hepatic route)?
2-3 days
When you give an inhibitor how long till you see its effect on clearance?
couple hours
What are the three things that can affect the drug movement in our out of the kidney?
- Glomerular filtration gets rid of it
- Active Tubular Secretion
- Tubular reabsorption (down its concentration gradient)
The more _____ in a dosage interval the greater the fluctuation
half lives
In clinical situations, the amount of fluctuation that can be tolerated for any given drug is
determined by what?
Its therapeutic index
Describe zero order kinetics
the process in which the rate of elimination of drug from the body is independent of the amount of drug in the body (NOT first order). The AMOUNT of drug removed per unit time is constant, i.e., is independent of drug concentration
zero order kinetics is most often due to what process?
Most often due to saturation of hepatic metabolic processes (esp. phase II conjugations)
What drugs operate at zero order kinetics?
- aspirin
- phenytoin
- ethanol
Why do proteins represent majority of binding sites for drugs?
Proteins allow the greatest amount of specificity
Name four types of drug targets
- Receptors
- Ion channels
- Enzymes
- Transporters
What features determine a drugs binding affinity to a certain receptor?
Size
Shape
Electrical Charge
Anatagonist role?
binds to receptor and does not bring a response. **You need the presence of an agonist in order to verify that the antagonist drug is working.
The greater the agonist tone…
The greater the effect of an antagonist
Define therapeutic efficacy
maximum effect
Define potency
dose of drug
concentration (EC50) or dose (ED50) required to produce 50% of the individual drug Emax
What does the dose-response curve assume?
Assumes that response is proportional to receptors occupied by drug
Potency of a drug is dependent on what two factors?
The affinity (Kd) of receptors for binding the drug and in part on the efficiency of this drug-receptor complex to generate a response [the intrinsic efficacy of the drug]
What variable provides information on how much drug (dose) will be required to produce a given effect?
The potency, EC50 or ED50
Maximal Effect or Maximal Efficacy [Emax]
reflects the limit of the dose-response relationship on
the response axis (y-axis).
It indicates the relationship between binding to the receptor and the ability to initiate a response at the molecular, cellular, tissue or system level.
What is the most important determinant of clinical utility?
maximal effect aka power
What happens to the efficacy of a drug when there is an agonist and you add a partional agonsit as well?
The efficacy goes DOWN. Less efficacious drug now occupying
What is more important… to have a more efficacious drug or a more potent drug?
Efficacious drug. You want the drug with the most POWER!
What type of drug t inhibits the action of an agonist but has no effect in the absence of an agonist?
antagonist
Define a receptor antagonist
bind to the same receptor as the agonist
Another term for receptor antagonist?
pharmacologic antagonist
What is a chemical antagonist?
binds directly to the agonist and does not interact with the receptor at all
What is a physiological antagonist?
binds to a different receptor than the agonist.
What effect does a competitive antagonist have?
Decreases potency (EC50 increases, dose or concentration increases) Efficacy remains the same (Emax)
What effect does a competitive antagonist have on the drug receptor graph?
Shifts to the RIGHT! decrease potency
Emax remains the same
Metaprolol
a pharmacologic antagonist of norepinephrine.
Blocks the cardiac Beta 1 receptor
What are the effects of Noncompetitive Irreversible Antagonists?
Increasing agonist concentration can NOT overcome.
The antagonist binds to the receptor and decrease the number of available receptors.
Emax decreases. Efficacy goes DOWN
No change in potency
Describe a Quantal dose-response (effect) curves
characterizes pharmacologic responses that are all-or-nothing events (quantal, not graded) in a population of subjects (not an individual).
Quantal dose-response vs. Graded dose-response curves
Quantal dose-response curves are NOT used to determine Emax.
Define the ED50 in a graded dose response
The ED50 is the dose that initiates the response in 50% of the test population.
Benefit of using a quantal dose-response curve?
provide info on drug safety by comparing therapeutic responses to toxic responses
A higher therapeutic index indicates:
a safer drug
What is the therapeutic index range for most drugs?
10-20
What does standard safety measure look at?
The extremes of a population.
Percent by which the dose effective in 99% of the population (ED99) must be increased to cause death
(or a selected side effect) in 1% of the population (LD1 or TD1)
True or False: Quantal dose-response curves can provide information on relative drug potency?
TRUE
Extension effects
category of adverse reaction
Arise from an extension of the therapeutic effect and are dose-related and
predictable
side effect
category of adverse reaction
Predictable, dose-dependent reactions that are unrelated to the therapeutic goal. Can be produced by the same drug-receptor interaction responsible for the therapeutic
effect, but at different organ or system
Idiosyncratic reactions
Genetically determined abnormal response to a drug. **Unpredictable.
Drug allergy
Adverse response of immunologic origin, unpredictable, severity is dose independent.
What are the effects of Pharmacokinetic drug interactions
s can result in elevated drug concentrations (via reduced elimination rates or protein-bound drug displacement) leading to toxicity OR they may cause decreases in plasma
concentrations (via more rapid drug elimination or decreased drug absorption) leading to levels below
therapeutic effectiveness.
What are the effects of pharmacodynamic drug interactions?
ns at the receptor level can result in
pharmacologic or physiologic enhancement or antagonism of a drug’s action. DOES NOT CHANGE PLASMA DRUG CONCENTRATION
What is one key difference between pharmacokinetic and pharmacodynamic drug interactions?
pharmacodynamic drug interactions do NOT change plasma drug concentrations!
What do you use to inhibit the rate-limiting enzyme, alcohol dehydrogenase?
ethanol and fomepizole
For the majority of poisoning cases, the mainstay of treatment will be
support of vital functions
What are the results of methanol poisoning?
visual disturbances due to effects of formic acid on optic disc and retina. Death from methanol is almost always
preceded by BLINDNESS and results from sudden cessation of respiration.
What are the results of ethylene poisoning?
damage to the kidneys due to deposition of **calcium oxalate crystals leading to acute renal failure in most patients.
What is the rate limiting enzyme in the methanol and ethylene pathway?
alcohol dehydrogenase
What is fomepizole used for?
used to treat methanol and ethylene poisoning by inhibiting alcohol dehydrogenase
How is ethanol used to treat methanol/ethylene poisoning?
Ethanol functions as a competitive inhibitor of alcohol dehydrogenase, saturates the enzyme, and
reduces production of formic acid from methanol and oxalic acid from ethylene glycol
What is the percentage breakdown for the acetaminophen metabolic pathways?
70-80% of acetaminophen metabolized via phase II glucuronic or sulfate transferase
5-19% metabolized via phase I cytochrom p450 CYP2E1
What is the sequence of metabolic events that results in hepatocellular injury due to acetaminophen poisoning?
saturation of the phase II sulfate and glucuronide conjugation pathways by toxic doses. This results in excessive formation of N-acetyl-p-benzoquinonimine (NAPQI) by the unsaturated phase I P450 pathway, eventual depletion of cellular glutathione for detoxification, and the binding of NAPQI (Ac*) to critical protein or cellular constituents
N-acetyl-p-benzoquinonimine (NAPQI)
is the toxic metabolite that is made via the phase I metabolism of acetaminophen via CYP2E1
What are the Predisposing factors for hepatocellular damage?
increased CYP2E1 activity and decreased hepatic glutathione content (both occur with excessive alcohol consumption)
What is the early treatment for acetaminophine poisoning?
activated charcoal and gastric lavage
How would do you treat a patient after 12-36 hours of ingestion of acetaminophine?
N-acetylcysteine serves as a precursor for glutathione synthesis, providing a source of cysteine (the limiting amino acid precursor). N-acetylcysteine also functions as a nucleophile to
capture NAPQI produced from residual acetaminophen
What poisoning interventions acts via inhibiting toxication?
fomepizole
What poisoning interventions acts via enhancement of detoxification?
n-acetylcysteine
At what step do you want to make sure your generic drug is bioequivalent to the brand name drug?
Absorption
