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149 Cards in this Set

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final common pathway of gastric acid production is
proton pump H+/K+ ATPase exclusive to the stomach
first established involvement of a receptor in the induction of drug-metabolizing enzymes.
Aryl hydrocarbon Receptor (AhR)
Any gene that is considered a Xenobiotic response element (XRE) will respond to what receptor?
AhR
Genes induced by AhR
CYP1A1, some Phase 1 and phase 2 enzymes
What compounds can bind to AhR?
Dioxin
benzo(a)pyrene
hydrocarbons
indole-3-carbinol
What receptors induce these enzymes?
CYP2B:
CYP 3A:
CYP4:
Constitutive androstane receptor (CAR)
Pregnane X receptor (PXR)
Peroxisomal proliferator-activated receptor (PPAR)

All of these enzymes have Retinoid X receptor as their coactivator.
__________is the term often used to integrate all the processes of distribution, biotransformation and elimination.
Disposition
total body water is into _____and ____ water.
Inter and extra cellular
T or F: Intercellular water is the body's biggest water compartment?
True!
the percent of body weight that is water will vary _______with the body’s fat content
inversely
What markers are used to measure total body water?
D20
Anti-pyrene
Alcohol
Dilution methods are used to determine what?
Volumes of various body compartments.
Volume of Compartment = Mass of X administered/Concentration of X
ECF compartment volume is typically measured how?
as 1/3rd of TBF
What percentage of plasma is H20? Protein?
93% water and 7 percent protein
T or F: The osmolality of plasma, interstitual fluid and intracellular fluid are essentially the same.
True!
Osmolarity is determined by the _________ of particles.
Total number (not charge!)
What 3 things can control the vascular smooth muscle of an arteriole?
nerve impulses from the autonomic nervous system
circulating vasoactive hormones
metabolites carried in the blood
The distribution of blood through the capillary bed of an organ is controlled by ___________.
precapilary sphincters, they contain smooth muscle
What blood vessels contain the largest portion of circulating blood (and serve as a reservoir of blood)?
Veins
What organ has the largest blood flow relative to its size?
The kidney
What organ is the best extractor of O2 from the blood?
The Heart
T/F: The arterioles are coated with smooth muscle?
True!
Name some functions of the endothelium
Filtration, contraction, relaxation, clotting, inflammation.
name the 3 types of capillaries
Macular (all capillaries expect those that are not fenstrated or OZ)
Fenstrated (kidney, pituitary, exocrine glands)
Occluding Zonule (in brain except for certain areas like the CV organs)
basement membrane only holds back molecules greater than _______ MW
about MW 45,000.
T/F: Astrocytes do not contribute to the BBB.
False
Two major lymphatic ducts.
the right lymphatic duct and thoracic duct
What valve controls the flow of digested material from the ileum into the large intestine?
ileocecal valve or sphincter
T/F: The absorption of most drugs happens at the upper part of the intestine
True
What prevents the passage of highly lipophillic drugs across the small intestine?
The hydrated glycocalyx coating around the microvilli. The microvilli of the small intestine are coated with a layer of glycoproteins called the glycocalyx. This layer facilitates water crystallization and formation of the hydrophilic barrier that surrounds microvilli.
Does Metoclopramide increase or decrease gastric emptying?
It speeds it up.
Food generally _______the rate of absorption.
Decreases
If EC theophylline is taken after a meal, what occurs?
"dose dumping" and toxic fx, theophylline should be taken on an empty stomach.
Severe diarrhea in a hosptial may be facilitated by the the use of what drugs?
Antibiotics.
Do adrenergic signals speed up or slow down digestion?
They slow it down.
The 3 most abundant enzymes in intestinal metabolism and transport are...
CYP3A4 (PI)
SULT1A1 (PII)
UGT1A1 (PII)
Gastric acid secretion is under the control of three principal agonists:
histamine, acetylcholine and gastrin
What effect does somatostatin have on gastic acid production?
It decreases acid secretion because somatostatin decreases histamine production.
Before a CAR ligand binds to CAR, what is CAR bound to?
An inverse agonist
Post-transcriptional induction is most pronounced for what CYP enzyme?
CYP 2E1
What are some inducers of CYP 2E1 post translational induction?
ethanol
organic solvents isoniazid
uncontrolled diabetes
What enzyme metabolizes felodipine and ethinyl estradiol?
CYP3A4
What are inhibitors and inducers of CYP3A4?
Inhibitiors: Grapefruit juice and certain antifungals

Inducers: Rifampin and St. John's Wort
What enzyme activates antiplatelet drugs such as clopidogrel?
CYP2C19
What condition can clopidogrel exacerbate?
Peptic Ulcers
What issue is there with administering a PPI like omeprazole with an antiplatelet drug?
Omeprazole inhibits 2C19 which is needed to activate the antiplatelet drug.
PPI use what enzyme for inactivation?
2C19
Omeprazole
What reaction activates minoxidil?
PII sulfation
APAP toxicity is exacerbated when glutathione levels fall how much?
By 90%
glutathione peroxidase reacts with what?
H202 and ROOH, decomposes them to H20
Oxidative damage is most pronounced in what type of lipid?
Unsaturated lipid chains
Benzene exposure causes what conditions?
Pancytopenia and aplastic anemia and leukemia
Myelodysplasia can transform into what?
Acute Myeloid Leukemia
How can you prevent Benzene's toxic effects?
Take something that competitively inhibits 2e1 and 2b6
Benzene metabolism starts where?
In the liver. It can then be metabolized in the bone marrow to even more toxic intermediates
Pericytes and cerebral endothelial cells contribute to what structure?
Cerebral extracellular matrix
The physical barrier that surrounds brain capillaries comes from what cell?
Astrocytes
What is the immunocompetent cell of the brain?
Microglia cells
The high number of efflux pumps in the brain's capillaries cause a greater need for what organelle?
Mitochondria
Why are the capillaries of the brain so highly occluded?
1. Occluding zonulae
2. Low number of transient fenestrae
What part of the brain forms the CSF?
The epithelial cells of the choroid plexus
How does the CSF get back into systemic circulation?
Through the arachnoid spaces on the brain -->large lymph vessel in neck --->lymph vessels to the heart
The area posterema is responsible for what?
It is a vomiting center that reacts to molecules within the blood. It is sensitive to chemotherapy agents.
Neurohypophysis does what? And what is it also called.
It is also called the anterior pituitary. It secretes neuropeptides into the blood and senses blood hormone levels using feedback mechanisms.
Why do the AP and NH need to be outside the BBB as Circumventricular organs?
They need to sense products in the general circulation that are otherwise filtered by the BBB.
What 3 things support the brain within the arachnoid?
Nerve roots, blood vessels, and arachnoid trabeculae.
What is Cushing's reflex?
It's when an increase in intracranial pressure triggers brachycardia to decrease systemic bp thus decreasing intracranial pressure.
normal cerebral blood flow is at what arterial pressures?
65-140 mm Hg
How can glutamate signal vasodilation in the brain's capillaries?
Glu triggers NMDA receptor on neuron --> Ca levels rise ---> NO synthatase activates producing NO --->NO causes vasodilation

It can also trigger glu receptor on an astrocyte--->Ca levels rise-->Phospholipase A2 produces Arachadonic Acid ---> Cyclooxygenase converts AA to prostalandin E2 (PGE2) --->PGE2 then causes vasodilation

This 2nd pathway can also be triggered by Noradrenaline
Absorptive mediated trancytosis can be activated by what type of molecule?
Negatively charged ones
What are the three transport systems in the BBB?
Carrier Mediated Transport
Receptor Mediated Transport
Active Efflux Transport
Why do phenobarbital and phenytoin pass less readily across the BBB than expected?
Plasma protein binding
Why do glucose, L-DOPA, and phenylalanine pass thru the BBB faster than expected?
They use specific carriers
Cleaving an antibody with papain produces what?
Seperate Fc and Fab regions. Compliment can't bind to whatever the ab regions bind to.
Cleaving an antibody with pepsin produces what?
Fab2 antibodies are produced as a result of this cleavage. It deletes the Fc region mostly but still allows something to bind to the shortened Fc portion. It inceases specificity.
In pts immunized against pertuss, what population is likely to get the disease though they've been inocculated and why
The elderly because they outlive their body's ability to respond to antigens (chromal exhaustion).
Name 1 way you can get natural passive acquired immunity?
Mother's milk
Name 1 way you can get artificial active immunity.
Vaccination
Artificially acquired passive immunity is often obtained how? When is it most practiced?
By injecting immunoglobulins from another person or animal, done mostly in situations of acute poisoning. It is also used as prophylactic for hypo-gamma-globulinemia
Risks w getting artificial passive immunity.
AIDs/Hepatitis if product is human
Serum sickness (antibodies produced vs injected abs, complexes damage capillaries)
Immunity doesn't last
Can attenuated vaccines be given to immunocompromised individuals?
Nope! They'll get the full blown disease.
Tetanus, Diptheria, Hepatitis B, and cholera all have what kind of vaccine?
Subunit vaccines
What is a toxid?
An inactivated toxin, the toxic portion has been removed and the antigenic portions are still intact.
Between live and attenuated vaccines, which provides longer immunity?
Live vaccines
How do allergy shots work.
They stimulate your immune system to produce more IgG and IgA which compete with IgE for allergen binding. This decreases the # of mast cells and increases the number of cytokines from Th1 cells.
In a viral infection, which interferons are made first?
Alpha and beta
Oral or injected IFN: Which can we use a lower dose with?
Oral
rIFN-B is used against what disease?
Multiple Sclerosis
rIFN-g is used against what disease?
granulomatous disease and osteopetrosis
In humanized antibodies, which part of the antibody is mouse?
The CDR ("hypervariable") region.
Bevacizumab specifically targets what?
VEGF
OMALIZUMAB targets what?
IgE, it binds to IgE so it can't bind to mast cells and basophils.
Most drugs bind to albumin, with a few (name three) exceptions:
1. Steroids
2. Thyroxines
3. Heavy metals
also vitamin B12, copper, and iron
Hepatic metabolism of drugs id determined by two main components
1. quantities and forms of dmes
2. blood flow to the liver and the perfusion of parenchymal cells
Propanolol, bound to serum proteins, is highly cleared by the liver. If the unbound fraction of the drug increases, the Vd (volume of distribution) increases and the half-life of the drug in the body increases. Why?
It takes a very small concentration of free drug to exact an effect, so a relatively small change in free drug greatly affects cells.
Debrisoquine is metabolized by what CYP enzyme?
2D6
S-mephenytoin, omeprazole, and nexium are metabolized by what CYP enzyme?
2C19
2D6 polymorphism is seen more in what population? 2C19?
2D6 - Caucasian (5-10% PM)
2C19 - Asian (15-20% PM)
What is the genetic basis of 2D6 poor metabolizers?
2 mutant 2D6 alleles which cause reduced or loss of activity
What is the genetic basis of 2D6 ultrarapid metabolizers?
Functional 2D6 alleles are duplicated or amplified (seen a lot with Ethiopians)
In a pt with UM 2D6, what will occur if they take codeine.
The codeine will be rapidly converted into morphine causing severe abdominal pain, euphoria, and dizzyness.
What is the major IM genotype in caucasian? Chinese? for 2d6
CYP2D6*41 (*10 in chinese)
what's IM phenotype?
PM frequency is highest in what population?
Vanuatu Pacific Islanders
After 1 dose of omeprazole, which group of 2C19 metabolizers has the greatest increase in gastric pH? How about cure rates for H. Pylori?
PM has the highest pH increase and highest cure rate
name some drugs metabolized by 2C9
Phenytoin (NOT mephenythoin, that uses 2C19)
Glipizide
S-Warfarin
A pt homozygous for CYP2C9*3 will be very sensitive to what drugs?
Warfarin, these patients have diminished clearance of S-Warfarin. These patients are also sensitive to phenytoin
What is the MoA for Thienopyridines?
They inactivate the PY12 receptor for Adenosine ADP and ATP through covalent binding.
If a drug has a low Vd, is it concentrated in the plasma or is it bound to something?
It will be in the plasma. And drugs with a high Vd are probably bound to something like skeletal muscle.
What agents bind to A1 globulin?
Steroids, B12, thyroxine
What agents bind to A2 globulin?
Cu+2 (ceruloplasm)
What agents bind to B1 globulin?
Fe+2 (transferrin)
Examples of drugs w a high extraction ratio? (HINT: PLMP)
propranolol
meperidine
propoxiphene
lidocaine
Examples of drugs w a low extraction ratio? (HINT AWPT)
antipyrine
warfarin
tolbutamide
phenytoin
Will drugs bound to albumin be filtered by the kidney?
No, albumin is too large to be filtered out.
What process in the kidneys allows for the most renal drug excretion?
Secretion using OATs and OCTs.
Much of reabsorption occurs in what part of the tubule?
Distal tubule
What is biological half life?
the time it takes to remove the drug from the entire body irregardless of how complex it is
Why is a standard dose of acetaminophen (per kg bw) less hepatotoxic in infants than adults?
They have less of the 2E1 enzyme that metabolizes APAP into the reactive NAQPI metabolite.
T/F
Sulfate conjugation is higher in infants than adults.
True
T/F
Glucuronide formation is lower in infants than adults
True
T/F

In general CYP enzymes are higher in infants than adults
False
Infants are more resistant than adults to the toxic effects of certain drugs:
1. Halothane
2. Isoniazid
3. APAP
mannitol, inulin, saccharose can be used to measure the water volume of what body compartment?
Extracellular compartment
Variation in the body's water content is primarily due to variation of what other body tissue?
Adipose
Pediatric idiosyncracy to aspirin results in this
Reyes Syndrome
Paradoxically, administering this to children helps to manage their ADHD
amphetamine! (a known stimulant to adults)

This is an example of how infants differ qualitatively and quantitatively from adults to drugs
T/F
Sulfation pathway in newborns matures in fetal development.
True
Why is there a lagtime between expression level and catalytic activity?
Enzyme levels are looked at by transcript analysis. You can make mRNA for a protein, it needs to be processed so newly synthesized mRNA is immature and inactive. So levels of mRNA don’t always reflect the amount of enzyme you get. Eg in 2C9, black bar represents mRNA but grey bar shows enzyme activity. Immature mRNA is not translated into protein until later on.
What is the last isoform to be expressed in human liver?
CYP 1 A2
This CYP isoform is expressed in Fetal Development
CYP 3A7
Name an isoform expressed in early neonatal period (Group II; within hours of birth)
CYP 2E1, CYP2D6
___________ binds mostly basic drugs.
Alpha 1- acid glycoprotein
__________ binds mostly acidic drugs.
Albumin
What is the consequence of having a higher volume of distribution in infants when administering a drug?
infants require higher (per unit of body weight) doses of such drugs than adults
What two factors contribute to the changes in membrane permeability in infants?
1. Immature BBB
2. Lower expression of drug efflux pumps
Due to the ______ nature of infant's intestional pH, neonates absorb (weak acids/ weak bases) poorly
basic; weak acids
Thalidomide teratogenicity is restricted to __________ weeks of embroynic development because the limb bud development is most active during these periods.
4th and 5th.

"Molecular basis of the developmental-stage specificity in the effects of teratogens
- The “time window” of vulnerability"
What controls the smooth muscles within arterioles?
autonomic nervous system
circulating vasoactive hormones
metabolites

Venules are also controlled by the autonomic NS.
Pts who have had chemo and are deficient in GSTP1 tend to get what disease?
t-AML (therapy related acute myolgenous leukemia)

This occurs because GST is needed to detoxify the toxic intermediates of chemo drugs like cyclophosphamide
Why does susceptibility to Aflatoxin-induced liver cancer increase in pts deficient in GSTM1?
Because GST is needed to detoxify the alftatoxin epoxide. This also applies to susceptibility to tobacco-related respiratory cancers. Smoke needs detox by GSTM1 or DNA damage occurs.
Loss of function mutations in MRP2 results in what condition?
conjugated hyperbilirubinemia-
aka Dubin-Johnson syndrome (DJS).
MRP2 is responsible for pumping what species out of the liver into the bile duct?
Organic anions and conjugated bilirubin
What is the difference between Dubin-Johnson Syndrome v. Crigler-Najar Syndrome and Gilberts Syndrome
DJ is conjugated hyperbilirubinemia
Gilbert's is MILD unconjugated hyperbilirubinemia
CN is SEVERE unconjugated hyperbilirubinemia
Examples of Killed Whole Organism Vaccines
Cholera, Flu, Bubonic Plague, Hep A
Examples of Toxoid Vaccines
Tetanus and diphtheria
The four variants of the B2AR are caused by what kind of mutation and result in what changes to the receptor?
Non synonomous mutuation (aa changes)
1. more sensitive to drug mediated downregulation
2. less sensitive to .....
3. n/a
4. loss of receptor fcn due to poor coupling to g-protein
Drug-Induced cardiac arrhythmia can be caused by what mutations?
Voltage gated ion channel mutation in the heart (May affect Na channel, K channel
Hemolytic anemia can be induced in patients lacking G6PDH when they take this drug or eat this food.
Primaquine, fava beans (both have quinones in them)
NO in the presence of superoxide will form what?
peroxynitrite