Class: Fundamentals II
Professor: Pillion
Date: 12/03/10
1
Scribe: Ashley Russell
Proof: Louisa Warren
Drug Targets and Classes Lecture:
XLII. 2nd generation Antihistamines: [S42]
a. you will need to know chemical names for test purposes; we won’t use brand
names at all. Once in a while, if the brand name is common I’ll add it along with
the chemical name to give you a clue. But need to know chemical names!!
b. 2nd generation antihistamines are rapidly absorbed, have a long duration of
action. They were designed to be a once a day drug. (Most common are once a
day versions of the drug)
c. They are designed to be given orally.
d. They don’t get in to the brain, don’t cause much sedation.
e. The first ones to come out were metabolized by the cytochrome P450 system
o P450: a family of enzymes found in the liver. They will add and remove
oxygen, oxidize and reduce. They basically take care of a lot of drug
metabolic drug processes.
o If you have a patient who is taking one of these antihistamines
chronically, and you give them a new drug (i.e an antibiotic to prevent
oral infection). What can happen, is that both of these drugs will get
metabolized by the same cytochrome. So, the metabolism of one drug
can affect the metabolism of the second drug. The net effect might be
that you end up outside the effective dose range for one or both drugs so
you need to adjust the dose. When you give a new antibiotic, you need
to check out that drugs metabolic profile and know which cytochrome
P450 breaks it down.
o 95% of the drugs you give to people give inactivated by the cytochromes.
o 5% of drugs are pro-drugs and will get activated by CYP450.
o Is important to know if drugs are activated or broken down by the
cytochromes and knowing which other drugs a person might be taking
that would go through the same metabolic pathway.
XLIII. Second Generation Antihistamines: [S43]
a. The most common ones are cetirizine, loratadine and fexofenadine.
o Fexofenadine came out first and has to be given twice a day. Is probably the
least popular.
o Cetirizine and Loratadine are given once a day, are more popular and are pretty
effective as antihistamines.
XLIV: Ocular Topical Antihistamines: [S44]
a. There are ocular version of antihistamines: olopatadine and levocabastine.
b. If you use these, you will “get the red out” if you will; are going to counteract the effect
of histamine, which causes vasodialation, tearing and redness of the eyes.
c. There are side effects associated with these drugs as well (See slide!)
XLV: Allergic Conjunctaivitis: [S45]
a. Allergic conjunctivitis can be treated with some of these antihistamines. They can also
be treated with mast cell stabilizers, which block the release of histamine or with a drug
that binds the binding of histamine.
XLVI: Nasal Topical Antihistamines: [S46]
a. Fluticasone is used a lot and Flonase is a popular brand (you don’t need a
prescription for it)
b. Fluticasone is used in the treatment of asthma and to prevent the onset of an asthma
attack.
Class: Fundamentals II
Professor: Pillion
Date: 12/03/10
2
Scribe: Ashley Russell
Proof: Louisa Warren
XLVII: REVIEW [S47]
a. Which of the following drugs is least likely to cause sedation?
a. All four of these drugs are antihistamines.
b. On another test question, might see one of these drugs and have to ID which
is an antihistamine.
XLVIII: REVIEW [S48]
a. Answer: Cetirizine.
a. A second generation drug and its given orally once a day and doesn’t cause
sedation.
XLIV: REVIEW [S49]
Which of the following mediators causes immediate symptoms after IgE is cross-linked by
allergens?
a. To give you a clue, those allergens are usually found on the IgE surface receptors
which are found on mast cells.
L: REVIEW [S50]
ANSWER: Histamine
LI: REVIEW [51]
Which of the following is not a systemic effect of histamine?
a. What do you associate with histamine? Do you associate gastric acid secretion?
YES. The antihistamine drugs that block gastric secretions block H2 receptors. H2
receptors are present in the gastric secretion.
b. Constriction of small blood vessels? Usually they dilate.
c. Bronchoconstriction? Yes
d. Formation of Edema? Yes.
LII: REVIEW [52]
ANSWER: Constriction of small blood vessels.
SWITCH LECTURES: Leukotrienes, NSAIDs and Gout (12.03.10)
I.
Leukotrienes, NSAIDs and Gout (INTRO) [S1]
a. We will spend more time talking about the NSAIDs because you don’t see as much
gout in your practices. Occasionally we have patients with gout who are taking a
specific therapy (NSAIDs)
b. NSAID: non-steroidal anti-inflammatory drug
i. These drugs are not steroids.
ii. There are inflammatory drugs that ARE steroids. To inhibit inflammation can use a
steroid or non-steroid. Sometimes one is better than the other.
II. Overview [S2]
a. Read slide
b. Acetaminophen doesn’t really fit under the umbrella of an NSAID, but it is an antifever and anti-pain drug so its usually included in the discussion of NSAIDs because
they are used as anti-fever and anti-pain drugs as well as anti-inflammatory drugs.
III. Inflammation S3]
a. what is inflammation?
i. A dynamic vascular and cellular response to insult or injury
ii. Your body gets some sort of insult and then responds to it.
b. A hangover is not inflammation, but if you bang your knee into the door and it turns
red, im seeing inflammation.
c. Runners knee from 30 years of running is inflammation.
Class: Fundamentals II
Professor: Pillion
Date: 12/03/10
3
Scribe: Ashley Russell
Proof: Louisa Warren
IV. Inflammation [S4]
a. Can be caused by microorganisms, toxins, biochemical damage, heat cold, radiation,
trauma, immunologic hypersensitivity.
b. So, a lot of different things can trigger an inflammatory response.
c. Usually this response is good because it tells our brain that our body has been
injured.
d. Anti-inflammatory drugs relieve the symptoms of inflammation, recognizing that
sometimes this response isn’t good. (Some people argue inflammation is necessary
and appropriate for healing to take place)
V. INFLAMMATION [S5]
a. Read slide
VI. Sequence of Events in Inflammation [S6]
a. A table of the events that go on:
i. Change in blood flow
ii. Permeability change
iii. Hemostasis (or blood movement) is reduced and as a result you get swelling, pain,
redness, loss of function.
b. Read slide.
VII. Mediators of Inflammation [S7]
a. All of the drugs have their basis on interacting with the biochemistry.
b. Normally, our cell membranes contain phospholipids (the bilayer) with a three carbon
backbone called glycerol.
i. two fatty acids attached in the first two positions and a phosphate attached in the
third position. The phosphate has something else added to it (inositol, choline,
etc.)
ii. Usually, the fatty acid in the number 2 position is arachidonic acid.
iii. Arachidonic acid is very “special”. It has 20 amino acids and 4 double bonds
which makes it very floppy. It sits in the membrane as a precursor, waiting to be
released.
1. Phospholipase A2 releases arachidonic acid
2. The enzyme that releases inositol triphosphate from phosphotidal inosital is
a different phospholipase (phospholipase C). This enzyme is activated by
some of are adrenergic and cholinergic pathways.
iv. Phospholipase A2 cleaves off the free fatty acid, arachidonic acid and then inside
our cells we have lipoxygenase and cyclo-oxygenase 1 and 2.
1. we usually think of Cox 1 as being constituative (i.e its on at all times) and
cox 2 is inducible (gets ramped up at time of inflammation).
2. As a result of making more cox 2, you get more of the products that are a
part of the inflammatory process. This has some implications in drugs that
inhibit different enzymes.
v. If any of the three enzymes are blocked completely, some bad stuff can happen. If
you block one side of the pathway (either lipoxygenase or cox 1 and 2), you will
have more “stuff” going to the other side of the pathway which will create an
imbalance (can lead to toxicitiy)
vi. NSAIDs primarily work by affecting cox 1 and 2 side of the pathway.
c. 12:27
VIII. The Arachidonic Acid Cascade [S8]
a. A cartoon that shows a phospholipid bilayer membrane. Phospholipase A2 cleaves
off this arachidonic acid.
b. Beacause arachidonic acid has 4 double bonds, it doesn’t lay flat in a long straight
line (will flop over on itself).
i. So, two types of enzymes can interact with it (one will form a ring structure and the
other wont)
Class: Fundamentals II
Professor: Pillion
Date: 12/03/10
4
Scribe: Ashley Russell
Proof: Louisa Warren
ii. The name “cyclooxygenase” means that you form a cyclized compound. This is
what prostoglandans are made of.
1. Ex: prostacyclin, PGE2, PGD2, PGF2, Thromboxane A and Thromboxane
B.
2. Each one is a different chemical derivative with different actions at different
sites in the body. But, lots of different cells will interact with many different
ones at the same time.
c. Lipoxygenase will give you an intermediate called “ETYA”, then you go down this
path and form leukotriene A which gets converted to leukotriene B, C, D and E.
IX. Picture (NO TITLE) [S9]
a. A better cartoon
b. At the top left is a cell.
i. Outer and nuclear membrane.
1. (Nucleus is purple, cytosol is in green and outside the cell is in yellow)
c. In this picture, the site of action of Phospholipase A2 and the release of arachidonic
acid is the nuclear membrane.
i. The arachidonic acid gets acted upon by liooxygenase and produces luekotriene
A4.
1. Leukotriene A4 gets converted to LC4 and LB4
2. These are fatty acid derivatives (lipid soluable) and can leave the cell, go in
the blood stream and look for cells with receptors to these chemicals.
d. The cell at the top right is in the blood stream and interacts with the leukotriene and
chemotaxis takes place as a result of the leukotrieneB binding on that cell. This cell
will change its outer shape and will interact with other cells causing a cascade of
cells in the blood stream
e. The airway cell in the bottom right corner has a receptor for a different leukotriene.
(either C, D or E). All of these are formed in the blood stream and can react with this
receptor. This is a leukotriene 1 receptor and causes smooth muscle constriction.
1. In an airway cell, you would actually have bronchoconstriction as a result.
Bronchoconstriction is one part of inflammation that we don’t want.
f. Two families of drugs you need to know about.
i. Zileuton: inactivates 5-lipoxygenase. So if you give somebody zileuton, they
won’t make leukotriene A4 (or any of the others). So, it’s a pretty good drug. Can
also have side effects. Leukotrienes have beneficial effects in certain parts of the
body so we’re shutting down both the good and the bad (it’s like “throwing out the
baby with the bathwater”).
1. Side effects: increases the movement of chemicals through the other side
of the pathway (the cyclooygenase pathway)
ii. Monteleukast, Pranleukast and Zafirleukast: these drugs interact at the level of
the receptor. Look like leukotrienes, and interact and block binding of leukotrieins
to the receptor. They work in a different way from zileuton.
1. These don’t interfere with Leukotriene production, but interfere with
leukotriene binding.
2. This gives you more leeway; and allows you to design drugs for specific
receptors that will affect specific parts of the body.
iii. Example test question:
1. “Which drug is a lipoxygenase inhibitor and which drug is a receptor
blocker?”
a. zileuton is the lioxygenase inhibitor and the leukasts are the
receptor blockers.
X. Actions of LTC4 (LTD4, LTE4) [S10]
a. Actions of LTC4:
i. Late onset, causes bronchoconstriction, increased vascular permeability so you
get edma, arteriolar constriction
XI. Leukotriene Antagonists [S11]
Class: Fundamentals II
Professor: Pillion
Date: 12/03/10
5
Scribe: Ashley Russell
Proof: Louisa Warren
a. Zileuton:
i. Read slide
ii. 600 mg 4 times a day.
iii. Will interact with warfarin. If you put them on this drug, can have a disastrous
interaction between the two drugs.
iv. Many patients who have a heart attack or valve replacement surgery get placed on
long term warfarin therapy. Zileuton (among others) can cause their metabolism to
change.
1. If a person is on an anti-coagulant and that level gets too high, that person
can have a bleed that wont stop. Can have an intercerebral bleed and die.
Or, if levels get too low, can have a thrombis form and cause an embolism.
(don’t want warfarin levels to get too high or too low!)
XII. Leukotriene Antagonists (part 2) [S12]
a. Read slide
b. Zafirlukast: given twice a day. Not as popular as some others. Can also interact
with warfarin and cause liver damage.
XIII. Leukotriene Antagonists (part 3) [S13]
a. Read slide
b. Montelukast: is given once a day (most popular).
XIV. ARS Question [S14]
a. Which of the following drugs inhibits 5-lopoxygenase?
XV. Which of the following drugs inhibits 5-lipoxygenase? [S15]
a. ANSWER: Zileuton.
XVI.
Nonsteroidal Anti-inflammatory Drugs (NSAIDS) [S16]
a. NSAIDs are the other half of the pathway, the side that deals with prostoglandin
formation.
b. Read slide
c. Salicylate was a precursor for aspirin.
d. Will see patiens on more than 10 different NSAIDs. A wide number out there.
i. They are each from different chemical families.
e. Lots of chemical structures that can block prostoglandins synthesis.
f. Not addictive, sedative, and don’t cause respiratory depression (yay!).
g. At low doses they have analgesic properties, and at high doses they have antiinflammatory effects.
i. If you want an anti-inflammatory response from aspirin, can’t take just one baby
aspirin a day.
XVII. NSAIDs Mechanism of Action [S17]
a. Recognize that glucocorticoids block the action of phospholipase. They block
everything! They are not NSAIDs. NSAIDs block the action of cyclo-oxygenases.
XVIII. Roles of COX-1 and COX-2 [S18]
a. Cox 1 is found in ceratin places where cox 2 isn’t.
b. Cox 1 levels are usually the same even if there is no inflammation.
i. It plays ordinary and normal roles in the GI tract and stomach. It accelerates the
blood flow through the gastric lining of the stomach. If you inhibit this, blood flow is
impaired, and you put yourself at risk for gastric inhibition.
ii. In the platelets, will have more clots when cox 1 is active, and less clots when it is
inactive (is a pro-coagulant).
iii. Will maintatin blood flow throughout the kidney. If an NSAID is taken at too high of
a dose, can get renal shut down. Prostoglandins normally aid in blood flow
throughout the kidneys, so if you block prostoglandin production, blood flow
through the kidney decreases
c. The inducible form, cox 2, goes up when you have inflammation, pain, or fever. Cox
2 selective inhibitors have less effects on the GI and platelets, but will still have the
negative effects on the kidney.
XIX.
Effects of Prostaglandins [S19]
Class: Fundamentals II
Professor: Pillion
Date: 12/03/10
6
Scribe: Ashley Russell
Proof: Louisa Warren
a. Read slide
b. PGE2 is protective for your GI tract and stomach
c. PGF2 is important during pregnancy and can be given if trying to induce an abortion.
Causes strong uterine contractions.
d. TxA2= thrombxane
e. So, get inhibition AND stimulation of clotting. Need a balance between the two. If
you inhibit this pathway, need to be careful about platelet aggregation changes.
XX. Clinical Effects of NSAIDs [S20]
a. read slide
XXI.
Side-Effects of NSAIDS [S21]
a. Read slide
b. CNS effects are rare
c. GI intolerance and increased bleeding are the most problematic.
XXII. Gastroprotective Role of PGE [S22]
a. Read slide
b. Increased epithelial growth helps to repair damage or wounds.
c. If you inhibit PGE, will have a negative effect (as far as the gastroprotective roles of
PGE go).
XXIII. Graph [S23]
a. Does this GI toxicity represent a clinical problem?
b. NSAIDs cause more deaths in the US than AIDS.
c. Tens of thousands of people die every year from NSAIDs overuse
i. Leads to GI bleedouts.
ii. Those that do survive, lead to an enormous cost burden.
XXIV. Renal Complications of NSAIDs [S24]
a. Read slide
b. Hyperkalemia = high potassium.
XXV. Common Drug Interactions S25]
a. can interfere with loop diuretics and thiazide which can effect how much urine we put
out.
b. SSRI: selective seratonin reuptake inhibitors (given for depression)
i. The metabolism of SSRIs and Beta Blockers is the same as for NSAIDs, which
can cause problems.
c. Before you recommend that a patient take ibuprofin for pain, make sure you look and
see what other medications they are taking.
XXVI. Nonselective COX inhibitors [S26]
a. These are different families of drugs; this list will increase the longer we are in
practice.
b. Some are very common, and others are used in specific niches.
i. i.e indomethacin is used commonly in the treatment of gout as opposed to
ibuprofin which is used more commonly for a headache.
XXVII. Properties of NSAIDS [S27]
a. Don’t have to memorize this chart, just recognize that there are drastic differences.
b. Aspirin is sort of an outlier with a very quick halflife.
i. Aspirin is checmially the acetylated form of ***************
ii. That acetyl group makes it unique; can covalently bind to cyclooygenase and
irreversibly inhibit it.
1. Every other NSAID is a reversible inhibitor of COX
2. This means that if I take a small dose of aspirin, the dose is high enough to
interact with platelets and will interact the cyclooxygenase and irreversibly
inactivate it. So, if a person has been taking aspirin, they will have a
decreased clotting. Only way to recover is to make new platelet. To get a
total turnover of new platelets, will take about a week.
3. This is not a complete shutdown of the clotting pathway, but diminishes one
arm of the clotting pathway.
Class: Fundamentals II
Professor: Pillion
Date: 12/03/10
7
Scribe: Ashley Russell
Proof: Louisa Warren
4. Should get patients to stop taking aspirin about a week before a surgery.
XXVIII. Aspirin (ASA) [S28]
a. Read slide
XXIX. Aspirin (ASA) part 2 [S29]
a. If somebody ties to kill themselves with Aspirin, will get vomiting, tinnitus (ringing in
the ears), decreased hearing, body temperature will go up, cardiac palpitations, and
eventually will die. This is a common mechanism of suicide.
b. Will want to pump the stomach or give activated charcoal to try and bind the aspirin
in the stomach before it gets absorbed.
c. If you make the urine more basic, can increase the removal of aspirin from the blood
stream.
d. Most kids with a fever are given Tylenol (acetaminophen) over aspirin because of
Reye’s syndrome.
XXX. Ibuprofin S30]
a. Read slide.
b. Have to go up to higher doses to get the anti-inflammatory affects.
XXXI. Other commonly prescribed NSAIDs [S31]
a. Read slide
XXXII. Risk Factors for Serious NSAID GI toxicity [S32]
a. Old people with a lot of aches and pains who take a lot of aspirin are the ones more
likely to suffer from NSAID toxicitiy.
XXXIII. CNS complications of NSAID use [S33]
a. Read slide
XXXIV. Inflammation and NSAIDs Summary [S34]
a. Read slide
XXXV. NSAID drug Interactions [S35]
a. Read slide
XXXVI. Selective COX-2 inhibitors
a. introduced a few years;
b. minimal effects on platelets and GI tract
c. Still have negative effects on the kidneys
XXXVII. Selective COX-2 inhibitors:
a. Celecoxib, rofecoxib and valdecoxib
b. Rofecoxib and valdecoxib have been recalled because of cardiovascular events
c. Celecoxib is still on the market and is very carefully monitored and has a black box
warning (could be dangerous, so it’s not used that much).
XXXVIII.
Roles of Cox I and Cox 2:
a. Cox 2 is both inducible and constitutive. We want to block the inducible Cox2.
b. The constitutive one goes along with it, unfortunately, so you get renal problems.
XXXIX. Cox-2 selective NSAIDs
a. pictures.
XL. Cox-2 Inhibitors
a. read slide
XLI.
Acetaminophen:
a. Not a very good anti-inflammatory
b. Usually the test question that you get with acetaminophen is:
i. What is its toxicity? Why is it different?
1. Hepatic (liver) and is different because it’s not a good anti-inflammatory.
People try to overdose and die becauses of liver damage.
XLII.
Acetaminophen:
a. Read slide
b. Is metabolized in the liver by glucuronidation or GSH conjugation.
c. Toxic because it uses up all the GSH (normally, body has enough GSH to metabolize
it all, but if you don’t have enough GSH, the acetaminophen will bind to the proteins
in your liver.
Class: Fundamentals II
Professor: Pillion
Date: 12/03/10
8
Scribe: Ashley Russell
Proof: Louisa Warren
i. Acetylcystein is the antidote.
ARS Question:
a. Thromboxane A2 is responsible for which biological effect?
b. Different prostoglanins have different effects.
XLIV. Review:
a. ANSWER: D, platelet aggregation.
XLV. ARS Question:
a. Which one of the following drugs can cause vomiting, tinnitus, and vertigo at high
doses?
XLVI. Review:
a. ANSWER: Aspirin
XLVII. Gout
a. A unique form of irritation from the build up of uric acid in the blood stream
b. The levels of uric acid get so high that you get a build up of monosodium urate
crystals
c. So much of the salt builds up that you form a crystal (not a good thing to have in your
body)
i. Crystals will get in the way and cause inflammation and pain.
ii. Cardinal sign is that the big toe gets red and inflamed from the presence of uric
acid crystals
d. There isn’t a lot you can do to treat it, but can give NSAIDs to help the inflammation.
e. Two ways to treat gout:
i. Decrease the amount of uric acid that you make:
1. Enzyme pathway can be inhibited by Allopurinol
a.
ii. Also, can get more uric acid to come out of your urine called Probenecid
1. Increases uric acid excretion.
iii. Can give a person with drugs because they work differently
f. Colchicine: not really an NSAID, but binds to microtubules and prevents cells from
changing their shapes.
i. Turns out, that if a person is on that drug, they won’t mount an inflammatory
response as well as a person who is not on that drug.
ii. Doesn’t cure gout, but can give some relief. Especially useful if given within 24
hours of an attack.
XLVIII. Gout: Pathogenesis:
a. High levels of uric acid is called hyperuricemia.
b. Problem in gout: People will over produce uric acid or decrease their excretion of
gout.
XLIX. Gout Pathogenesis:
L. Uric Acid Synthesis:
a. Enzyme that is involved in producing uric acid is xanthine oxidase  this is the site
of allopurinol activity.
LI. Clinical Presentation of Gout:
a. In the big toe
LII. Management of Gout:
a. Management will include:
i. Indomethacin, colchicine and glucocorticoids
1. Glucocorticoids like prednisone depleats their entire inflammatory
response.
LIII. Colchicine
Colchicine is the anti-mitotic drug and binds tubulin, given in the first 12-36 hours of the
attack.
a. Best if given in the first 12-36 hours
b. ASE: diarrhea is especially bad
LIV.
XLIII.
Class: Fundamentals II
Professor: Pillion
Date: 12/03/10
9
Scribe: Ashley Russell
Proof: Louisa Warren
LV. Uricosurics:
a. Will help to increase excretion of uric acid by increasing renal excretion
b. Probenecid and Sulfinpyrazone are two drugs in this family.
LVI.
Probenecid
LVII.
Sulfinpyrazone
LVIII. Allopurinol:
a. Decreases uric acid production
**Note: Dr. Pillion ran over these last several slides on gout very quickly. Most of the important
information though, is listed in the slides.
[End 49:50 mins]