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Worksheet #1 Bimm 118
Rebecca Sanders
The following is intended to give you some practice answering pharmacology questions. It is not intended
to be used solely as a study guide. Remember that questions on the exam come from the notes from class,
so be sure to know all material covered in class!
1. What is the difference between pharmacokinetics and pharmacodynamics? Also, give one example of
a condition associated with pharmacogenetics. What causes this condition?
See Notes!
2. Pain killers belong to what type of drug?
a. Therapeutic
b. Prophylactic
c. Palliative
3. A competitive antagonist
a) binds to the same site on the receptor as the natural ligand
b) binds the receptor irreversibly
c) elicits a response from the receptor
d) shifts the dose-response curve to the right
e) shifts the dose-response curve to the right AND down
4. What is the ED50?
The dose that elicits a predefined response in 50% of the test subjects
5. What is the difference between the efficacy and potency of a drug?
Efficacy refers to the capability of a drug, whereas potency compares the relative effectiveness of
two or more drugs. Efficacy has nothing to do with how much you take. Two drugs can have
similar efficacy, but different potency.
6. According to the diagram
a) both drugs have the same efficacy
b) Drug B has higher efficacy
c) have different potency
d) Drug B has the lower potency
e) Drug A is a partial agonist
7. Describe the process involved in patenting a drug (be descriptive!)
Phase I, Phase II, Phase III (see notes)
8. What are orphan drugs? What incentive was provided in the 1980’s to encourage their development?
Drugs that affect less than 200,000 individuals in the US. Orphan Drug Act of 1983.
9. What is one concern with taking dietary supplements (concerning their development process)? Give
one example of a dietary supplement discussed in class and what it has been proposed to be useful for.
No FDA approval process, no regulation. Ex: Leptoprin (weight loss)
10. What is involved in the preclinical trials portion of developing a drug? What is often a serious
limitation here?
Study effects in-vitro (cells/organs). Study receptor-binding characteristics. Move into in-vivo
animal model and then predict the potential therapeutic uses. Animal models are often limitations!
11. Define and describe three different types of toxicity testing that must be considered when developing a
drug.
Mutagenicity, Carcinogenicity, Reproductive toxicity, acute toxicity, subacute toxicity, chronic
toxicity. See notes for descriptions—be able to define these!
12. Give three routes of drug administration, describe an example of each.
Oral (pills, tablets, coated tablets, capsules…)
Topical/percutaneous (creams, lotions, eye drops, etc)
Rectal or Vaginal (birth control)
Pulmonal (inhalers)
Parenteral (needles, IVs)
13.
Describe the difference between external and internal drug distribution barriers.
External: Skin (epithelium), creates tight junctions to create an unbroken phospholipids
bilayer. Drugs must cross the lipophilic membrane to enter the body
Internal (Blood-tissue): permeation occurring mostly in the capillary bed, developed
differentially in various capillary beds (muscle, glands, gut, liver, CNS, placenta)
14.
Rank in order of bioavailability (highest to lowest):
i. Oral
ii. Transdermal
Intraveneous>Transdermal>Rectal>Oral
iii. Rectal
iv. Intraveneous
15.
Describe the difference between drug elimination through the kidney versus the liver. What is
meant by first-order kinetics when describing drug elimination? Draw a graph that has both first-order
kinetics as well as linear, zero-order elimination. Label all axes and lines that you draw!
Kidney=Filtration elimination, Liver=metabolism
First-order kinetics refer to the fact that the rate of elimination is
proportional to drug concentration.
16. Make sure you can understand how to derive the clearance of a drug. What is the equation?
Clearance (CL) [ml/min]:
= Rate of Elimination [mg/min] / Drug concentration plasma (CP) [mg/ml]
where Rate of Elimination [mg/min] = k [1/min] x CP [mg/ml] x Vd [ml] and
Elimination rate constant (k) [1/min] = ln 2 / t1/2 (=half-life)
(ln 2 = 0.693)
=> CL [ml/min] = Elimination rate constant (k) [1/min] x Vd [ml] = ln 2 x Vd / t1/2
•
It is the sum of all separate organ clearances:
CL = CLrenal + CLliver + CLother
•
Clearance is the volume of plasma cleared of all drug per unit of time (a constant for any given
drug [ml/min])
•
The actual quantity of drug [mg] removed per time unit [min] depends on both the clearance
[ml/min] and the concentration [mg/ml].
17. Drug X is given as a rapid, single i.v. infusion to a 50 kg individual. The volume of distribution (Vd)
for drug X is 2 L/kg. What is the predicted initial plasma concentration if a 500 mg dose is administered?
C=Dose/Vd. Therefore C=500mg/(50kg x 2L/kg)=> 500 mg/100 L or 5 mg/L.
18. Describe the difference between and maintenance dose. When is it most appropriate to use the loading
dose as an estimate of how much drug to give a patient?
Loading dose is used for drugs with a long half-life. Loading dose must fill the Vd to achieve the
target Cp. The maintenance dose refers to the the amoune that must replace the drug that is being
eliminated over time.
19. Describe what is meant by the therapeutic index. What two very important factors go into this
calculation? What are two problems with this measurement of the therapeutic range.
=Maximum non-toxic dose/Minimum effective dose. Does not take into account the variability
between indivs. LD50 reflects only deaths, not other toxicities. ED50 depends on condition being treated
and LD50 depends on the patients’ overall condition.
20. Describe the steps involved in Phase I and Phase II Reactions during drug metabolism.
Phase I=Convert parent group into more polar metabolite. Often adds functional group to drug. Phase
II=Conjugation with endogenous substrates to increase solubility in the body. Following these reactions,
the body can better metabolize the drug.
21. Describe 3 examples of enzymes that are P450 enzymes. Give one example of a polymorphism that
exists in the population that disrupts this interaction. How does the mutation affect this process?
PPAR ligands, CYP1, CYP2E, CYP2B
CYP2C19: Polymorphism that changes the ability of the enzyme to metabolize mephenytoin. Most
prominent in Asian population.
CYP2D6: Defect in demethylation of codein (6-10% of Caucasians)
22. Give 2 examples of reactions that would represent oxidation of a drug. (On a test, understand what
happens to the functional groups represented in the drug).
22. Provide 2 examples of drug-drug interactions. Provide 2 examples of drug-food interactions.
23. Describe 3 examples of Conjugation reactions. What is the most important reaction within this group
and why?
Glucuronidation most important, quantitatively affects most drugs.
25. What functional groups are affected by N-glucuronidation? What two are affected by OGlucurondiation? How about sulfation?
N=amines, amides, sulonamides
O=esters, ethers
Sulfation=alcohols, amines, and thiols
26.
________________ competes with _________________ during drug metabolism and
____________________ predominates at low substrate concentrations, while ___________________
predominates at higher concentrations. ________________ catalyze the transfer of sulfate to substrates.
Describe what an agonist/antagonist is. Draw a graph of a full agonist versus a partial agonist (label all
axes). On another graph, draw the curve of an agonist alone versus an agonist + a competitive antagonist.
How does this differ from the addition of a non-competitive antagonist?
Agonist=drugs or ligands for the receptor that provoke/inhibit a biological response. Increasing
[agonist] creates in increase in biological response.
Antagonist=blocks or reverses the effects of agonists. No effect on their own.
27. What is an inverse agonist?
Triggers a negative response, induces symptoms you are trying to treat. Good for reducing
baseline symptoms. Ex) diazepam—inverse agonists of benzodiazepine receptor (convulsants).
Review: Lectures 4-5
January 29, 2007
Transmembrane signaling is accomplished by only a few mechanisms:
– Transmembrane ion channels: open or close upon binding of a ligand or upon membrane
depolarization
– G-protein-coupled receptors: Transmembrane receptor protein that stimulates a GTPbinding signal transducer protein (G-protein) which in turn generates an intracellular
second messenger
– Nuclear receptors: Lipid soluble ligand that crosses the cell membrane and acts on an
intracellular receptor
– Kinase-linked receptors: Transmembrane receptor proteins with intrinsic or associated
kinase activity which is allosterically regulated by a ligand that binds to the receptor’s
extracellular domain
Calcium Signaling as a second messenger:
Type Properties
Location/Function
Blockers
Plasma membrane of many
High activation
cells; main Ca++ source for
Dihydropyridines; verapamil;
threshold; slow
L
contraction in smooth and
diltiazem
inactivation
cardiac muscle
Low activation
Main Ca++ source for
threshold;
w-Conotoxin
transmitter release by nerve
N
slow
(snail venom)
terminals
inactivation
Low activation Widely distributed; important in
Mibefradil; (verapamil;
threshold;
cardiac pacemaker and Purkinje
T
diltiazem)
fast inactivation cells
Q: Why would Verapamil decrease both the blood pressure and the heart rate?
•
Receptors not only initiate regulation of physiological and biochemical function but are themselves
subject to many regulatory and homeostatic controls.
• Controls include regulation of synthesis and degradation of the receptor by multiple mechanisms;
covalent modification, association with other regulatory proteins, and/or relocalization within the
cell.
• Modulating inputs may come from other receptors, directly or indirectly.
• Receptors are always subject to feedback regulation by their own signaling outputs.
Ways that Calcium can act as a secondary messenger:
1. Gradient across membrane (low inside cytoplasmic vesicles, high in extracellular areas)—makes
this a very sensitive signaling system. Slight changes in membrane permeability will result in
dramatic changes in the concentration of Ca2+. Extracellular can be a source for Ca2+ if needed.
2. Voltage operated calcium channels (uptake from extracellular portion).
3. Ligand mediated calcium channels (requires binding of a ligand)
4. Store operated calcium channels (emptying of intracellular storage compartments)
5. Ca stored by calsequestrin in the ER.
6. Removal of Ca:
a. Pumps (PM Na/Ca exchanger)
b. PM Ca-ATPase (2 Ca ions transported per ATP molecule hydrolyzed
c. SR/ER Ca-ATPase
d. Buffers
7. Ca Sensors
a. Annexins (interact with membranes in a Ca dependent manner)
b. EF-Hand proteins (high affinity Ca binding domain)
c. Calmodulin
d. Troponin C
G-Protein Coupled Receptors:
Receptors that cross the lipid bilayer seven times
G Proteins: Guanine nucleotide binding proteins, bind GDP and GTP, possess intrinsic GTPase
activity
Additional Control:
GAPs: GTPase Activating Proteins
GEFs: Guanine-nucleotide exchange factors
RGSs: Regulators of G-protein Signaling
Mainly target Phopholipase C- and Adenylate cyclase (converts ATP into cAMP)
Also functions to phosphorylate transcription factors (CRE/CREB) through Protein Kinase A
(PKA).
Nuclear Receptors:
Lipid soluble ligands that penetrate the cell membrane. Contain DNA-binding domains. Can act
as transcriptional activators or suppressors. Creates lag in response time (several signaling events must
occur before response can be generated).
Lecture 5
Arachidonic Acid Metabolism:
All derivatives of arachadonic acid. Mainly generated through the action of PLA2 and DAGlipase
Biological functions of PGs:
•
Vascular tone
•
Platelet aggregation
•
•
Uterus tone
Bronchial muscle
•
•
Gastric secretion
Temperature and pain
Relaxation: PGs E1, E2, F2 and I2
Constriction: PGs F2, TxA2
Increase: PGs E1, TxA2
Decrease: PGs E2, I2
Increase: PGs E1, E2, F1
Constriction: PGFs
Relaxation: PGEs
Inhibition: PGs E1, E2, I2
Increase: PGEs
Cytokine Receptors:
Classical Hormones (spread throughout body) and cytokines (locally restricted).
Handout #3—Practice Problems
Rebecca Sanders 2/5/07
1. Explain How TxA2 works in Arachidonic Acid Metabolism.
a. Increases energy which promotes platelet formation while restricting blood vessels--leads
to clotting of the blood. It has a very short T ½ which can be very advantageous because it
can be easily controlled.
2. Explain why Aspirin would be effective if taken once a day, but becomes dangerous if taken more
than once a day.
a. Aspirin is non-reversible and can result in ulcers during long-term use. It acts as a PG
inhibitor making the PG receptors less sensitive. If taken more than once a day, the
receptors never have time to recover, however if taken only once a day, this promotes
platelet recovery and PG receptors have time to recover (promoted over TXA2).
3. Explain how LTC4, D4 and E4 mediate an allergic reaction.
a. SRS-A mediates anaphylactic shock, 10,000 fold more potent than histamine, constricts
bronchi, dilates blood vessels. Severe allergies can trigger this reaction causing
anaphylactic shock or death. Causes a decrease in blood pressure and causes internal
organs to shut down.
4. Describe the differences and similarities between classical hormones and cytokines.
a. Classical hormones are produced by endocrine organs and target cells that are distant from
the site of synthesis. Hormones are generally carried by the blood stream and signal
through receptors coupled to G-protiens, ion channels, or receptors with enzymatic activity.
Cytokines act locally (autocrine or paracrine), have a shorter T ½ and mediate
inflammation processes. There is ususally one producing and effector cell.
5. Give a flow chart of how the nervous system is divided. Include the CNS, Parasympathetic,
Somatic, Sympathetic, Autonomous, and PNS aspects of the nervous system.
(went over in class—simple schematic showing how the nervous system is divided and
how it relates to the drugs we are studying)
6. Describe the differences between the parasympathetic nervous system and the sympathetic nervous
system. When do these two systems work together?
(also went over in class)
7. Explain the difference between the Muscarinic receptors and Nicotinic receptors.
a. Muscarinic=G protein-coupled, act on the CNS, gastric mucosa (M1), cardiac (M2),
smooth muscle (M3).
b. Ion channel coupled: muscle type, ganglion type, CNS type
8. What are the differences in direct parasympathomimetics and indirect parasympathomimetics?
Give two examples of both.
a. Direct=have affinity for M and N receptors and mimic AcCh. Act mostly on the M type
receptors with the exception of Nicotine)
b. Indirect= inhibit the activity of AcChase (enzyme that degrades AcCh) which causes an
increase in AcCh
c. To treat symptoms:
i. Promote parasympathetic pathways
ii. Block sympathetic pathways
d. Direct: Muscarinic PSM: Carbachol, Bethanechol, Pilocarpine, Muscarine
e. Indirect: edrophonium, parathion, carbamates (physosigmine, neostigmine), quaternary
alcohols, horny goat weed, organophosphates and nerve gases (irreversible)
9. Give one example of a parasympthomimetic/parasympotholytic that acts as an agonist and one that
acts as an antagonist. Explain in detail how each of these work.
a. Carbamates: Act as an indirect PSM. Inhibits AcChase, increasing the availability and T
½ of AcCh. Triggers M and N receptors.
b. Antagonist=parasympatholytics, can be muscarinic or nicotinic receptor blockers. Ex)
atropine which prevents hypersecretion of bronchial mucus. It is a muscarinic PSL
10. Which drug groups can be used to treat acid reflux/ulcers?
a. Pirenzepine (Muscarinic parasympatholytic)
11. What receptors are used in the sympathetic side of the nervous system and what are their
individual functions? What are three transmitters that are used in the autonomic nervous system?
a. : excitatory except in G1 (becomes inhibitory), : inhibitory except in heart (becomes
excitatory), 1: cardiac, 2: bronchi, blood vessels
b. Acetylcholine (all pre and post ganglionic neurons), Norepinephrine (Most sympathetic
post ganglionic neurons), Epinephrine (Adrenal Medulla—NO GANGLION)
12. Describe the process by which termination of norepinephrine can take place.
a. Reuptake into presynaptic nerve ending
b. Catechol-O-methyltransferase
c. Monoamino-oxidase
d. Presynaptic 2-receptors
13. Tranylcypromine and ephedrine both act through the adrenergic system, albeit through different
mechanisms. Describe the differences between how these two drugs act. What side effects can
occur from taking both of these drugs?
a. Both indirect sympathicomimetics. Tranylcypromine acts as an MAO-inhibitor (causes
more free Norepinephrine, or in the CNS MAO metabolizes dopamine and serotonin which
triggers increase in hormone levels—antidepressant). Irreversible inhibition of MAO (lasts
for weeks)
b. Ephedrine displaces norepinephrine in storage vesicles, which causes norepinephrine to be
released.
c. Side effects=hypertension, nerve damage, muscle injury…
14. Why are amphetamines very effective as an agonist in the adrenergic system? Why would
methamphetamine be more pontent as compared to some of the others in this drug family? Why
would someone who is taking methamphetamine become addicted to the drug?
a. 3 different pathways blocked—makes this very effective
i. Displace norepinephrine, inhibit norepinephrine re-uptake, inhibit degradation by
MAO
b. Methamphetamine is more lipophilic so that it can effectively cross the blood brain barrier.
Depletes norepinephrine catecholamine in vesicles, which can cause post use depression
and and gives it an addictive potential
15. Why would Clonidine have a sympatholytic effect, eventhough it is actually a sympathomimetic?
What does this drug treat?
a. Acts through an 2 receptor as an agonist, which inhibits neurotransmitter release through
incoming action potential. Activates presynaptic 2 receptors in the CNS which causes
reduced activity in the sympathetic nervous system. Treats hypertension.
16. Why does Dobutamine have such a strong clinical application for people with impaired cardiac
function?
a. Increases heart contractions without significantly increasing the heart rate, so you can
increase cardiac output (ionotropic effect) without causing a chronotropic effect. Acts
through 1-selective antagonist.
i. 1-selective: Mostly found in heart
17. What are some potential drug targets of antihypertensive drugs?
a. CNS, ANS (decrease sympathetic tone)
b. Heart (decrease cardiac output)
c. Veins (dilate)
d. Arterioles (dilate)
e. Kidneys (increase diuresis—secrete more H2O increasing viscosity of blood)
18. Assign the following drug name endings to the class of drug that they are:
a. stigmine=AcChase inhib
b. zoline=1 sympathomimetics
c. olol=-selective antagonist (sympatholytics)
i. Exception: LabetAlol: acts on 1 receptors as well
d. Dipine=L type selective Ca channel blocker
Review/Problem Set Lectures 9-12
Rebecca Sanders
1. Explain how Furosemide acts as a diuretic. What is the major side effect of this drug? Why is
Benzthiazide less potent as a diuretic? What can be done to prevent the side effects of taking these
types of diuretics?
a. Inhibits the NA+/K+/2Cl- symporter in the ascending limb in the loop of Henle. Major
side effect is loss of K+ and Ca++/Mg++. Results in Hypokalemia, hyponatremia,
hypochloremia, Hypotension and dehydration, Interaction with Cardiac Glycosides
b. Benzthiazide only inhibits Na+/Cl- symporter in the distal convoluted tube. Results in loss
of K+ and Mg++, not Ca++
c. Potassium can be given orally or IV. Also: Potassium-sparing diuretics: Often used in
combination with high-ceiling diuretics or thiazides due to potassium-sparing effects,
Produce little diuresis on their own
2. A patient arrives complaining of hypertension and it is later concluded that this patient is having
kidney problems. Furthermore, the patient explains that they are taking cardiac glycosides. What
type of diuretic would be best prescribed for this patient? Why?
a. Cant give loop diuretics or thiazide diuretics alone as both have an effect on K+
concentrations. Prescribe Potassium-sparing diuretics in combination with one of the
above. Not effective on their own. These use aldosterone to promote reabsorption of Na+
in exchange for K+ (transcriptionally upregulates Na+/K+ pump and sodium channels).
i. Ex: Spironolactone (Aldosterone receptor antagonist—onset requires several days)
ii. Ex: Amiloride/ Trimterene (Blocks sodium channels—quick onset)
3. In what instances would Mannitol be used? How is it administered and why?
a. Used to prevent renal ailure, causes a reduction of intracranial pressure. Selectively
increases water excretion without significantly increasing Na+ excretion. Increases
osmolarity of the blood, decreases amount of spinal fluid (treats brain swelling). Only
given by IV because it can crystallize (requires filter so that no crystals enter blood stream).
4. Why do our kidneys reclaim most of the uric acid filtered at the glomeruli? Why don’t humans
and apes break down uric acid? What potential concerns should a doctor have when prescribing
uricosuric agents?
a. Uric acid is a potent antioxidant and can protect cells from damage by ROS. Also, lethally
damaged cells release their uric acid crystals which enhances the ability of nearby dendritc
cells to present antigens released at the same time to T cells—leads to a stronger immune
response.
b. Humans/Apes have an inactive form of the gene that encodes uricase—cant effectively
break it down.
c. Uricosuric agents promote excretion and inhibit reabsorption of uric acid at therapeutic
doses, but inhibit excretion and reabsorption at subtherapeutic doses, which would lead to
an increase in uric acid production!
5. What effect would taking Probenicid have on a patient already taking Penicillin?
a. Causes long lasting Penicillin action. Probenicid inhibits the secretion of Penicillin into the
tubules and raises the plasma concentration.
6. Why would providing both Aluminum hydroxide as well as Magnesium hydroxide create a very
effective antacid? How would Cimetidine act differently?
a. When combined, side effects are offset. These are only neutralizers, do not prevent the
production of acid.
b. Cimetidine acs as an H2 receptor blocker (since Hist. normally stimulates acid production,
target receptor to prevent acid production.
7. Why would taking Ibuprofen over a long period of time eventually lead to an ulcer? What drug
might help reduce this side effect?
a. COX inhib, block PG production in stomach (and elsewhere), which leads to increased
acid. Increased acid leads to a reduction of the mucus layer, which can eventually cause an
ulcer.
b. To reduce side effect, take misoprostol which would cause a compensation of endogenous
PG in the stomach. You also could inhibit isoforms of COX, but this could lead to heart
issues.
8. Give three targets of Antiemetic drugs.
a. Histamine receptor antagonist, dopamine receptor antagonist, muscarinic receptor
antagonists…
9. Describe three types of laxatives (mechanisms/action/etc..). Give one example of a specific drug
in each group.
a. Bulk laxatives: causes reflex contraction (peristalsis) that propels the bowel content
forward Increase in bowel content volume triggers stretch receptors in the intestinal wall
i. Non-absorbable carbohydrates (Bran, Fiber)
ii. Osmotically active laxatives (Epsom salt)
b. Irritant laxatives = purgatives. Cause irriatation of the enteric mucosa => more water is
secreted than absorbed => softer bowel content and increased peristaltic due to increase
volume
i. Small bowel irritants (Ricinoleic acid and Ricin)
ii. Large bowel irritants (Anthraquinones, Bisacodyl, Sodium picosulfate)
c. Lubricant laxatives
i. Paraffin
ii. Glycerol
10. Describe the differences between Type I and Type II diabetes. What are three different ways to
treat diabetes?
a. Type I is insulin dependent, usually juvenile onset, autoimmune disease caused by
destruction of the beta cells. Requires exogenous insulin for treatment
b. Type II is insulin-independent, usually adult onset caused by target cell resistance to insulin
(InsR decreased, signaling defect), Usually in obese patients, treated with oral
hypoglycemic drugs.
c. Treatments: Make InsR more sensitive, Increase bodily production of insulin, provide
exogenous insulin.
11. Describe the differences between three different types of Insulin provided to diabetic patients.
a. Natural is unmodified human insulin, short duration (T ½=9 min), only given by IV, good
for emergencies
b. Insulin Lispro reverses aa 28 and 29 of Beta-chain. Increases action and prevents dimer
formation. Usually given right before meals.
c. NPH Insulin is regular insulin mixed with protamine (+charged protein) which leads to
delayed absorption (insulin is neg charged). Results in very long acting insulin.
d. Insulin Glargine (Lantus): aspasparagine at A21 replaced by glycine and two arginines
added to C-term. Low aqueous solubility at neutral pH, soluble at pH4. forms
microprecipitates causing slow release. Constant concentration over time profile (24
hours).
12. Describe 4 different routes of administration for Insulin.
a. Subcutaneous
b. IV
c. Jet injectors
d. Implantable insulin pumps
e. Intranasal insulin
f. Pulmonary insulin
13. In what cases would Tolbutamide be administered? What is the mechanism of action?
a. Type II diabetes. Tolbutamide is a sulfonylurea which stimulates insulin release (increase
sensitivity of beta cells toward glucose which blocks ATP gated K+ channel. This causes
membrane depolarization and Ca++ increase resulting in insulin secretion. Also causes
reduction in serum glucagons levels, increased insulin binding on target cells.
14. Describe the differences between Pioglitazone and Metformine in the treatment of diabetes.
a. Pioglitazone increases insulin sensitivity of target cells. PPAR agaonist which promotes
transcriptional increase of insulin, which increases glucose transporters and receptors.
Causes hypoglycemia, long half life (7hrs), active metabolites up to 150 hrs).
b. Metformine increases glucose uptake and inhibits gluconeogenesis in the liver, causes
diarrhea and nausea but not hypoglycemia. Lowers LDL and VLDL and is an appetite
suppressant. Not good for patients with liver or kidney disease.
15. Describe how Hyperlipidemia becomes a problem (mechanism of disease). What are some
potential targets for treatment of this disease?
a. Too much cholesterol causes damage of endothelial layer. Monocytes and macrophages
are recruited under the endothelial and smooth muscle cells. These cells consume and store
cholesterol which causes plaques to form between the endothelial and smooth muscle cells.
More and more cells infiltrate and eventually rupture the endothelial layer releasing
plaques into the blood stream. Eventually leads to thrombosis.
b. HMG-CoA reductase is a great target (rate-limiting enzyme in pathway). Can also target
PPAR (agonist). Fibrates decrease secretion and enhance lipoprotein lipase. Bile acid
binding resins prevent reabsorption and enterhohepatic recirculation of bile acids (increase
in hepatic LDL uptake and receptors)
16. Describe three different outcomes of steroid hormone synthesis in regards to the hydorxylases. If
there are 18 carbons in the hormone, what does this qualify as? What about 19?
a. C21 hyrdoxylase: Prevents hydrox of C17 (only mineralocorticoids)
b. C17 hydroxylase: Hydrox at C17 followed by Hydrox of C11 and C21 (sex hormones and
glucocorticoids)
c. P450-C17 alpha hydroxylase: produces 17-keto-steroids (sex hormones).
d. 18C=usually estrogen
e. 19C=usually androgen (Exception: PROGESTERONES!)
17. List 3 actions of glucocorticoids for treatment and 3 undesirable effects of increased
glucocortocoids.
a. Inhibit all phases of inflam reaction, promote fetal development, inhibit NFKB nuclear
translocation (proinflam mediators prevented), Upregulate lipocortin (no PG or LT
synthesis)
b. Bad: Immune suppression, increased glucose release, glucose converted to fat, increased
protein catabolism, salt and H2O retention, osteoporosis
18. What is the difference between Addison’s disease and Cushing syndrome? What could you use to
treat each?
a. Addisons: Lack of GC production, chronic fatigue and muscle weakness, loss of appetite,
low blood pressure, blood sugar abnormalities. Treatment= Hydrocortisone
b. Cushing: GC overproduction, upper body obesity, hypertension, water retention…
19. Why would a patient taking glucocortocoids see inflammation after stopping treatment? What are
4 examples of clinical uses for GCs?
a. Many negative feedback mechanisms (ex AcCh), if you stop taking the drug, body is not
able to resume GC production immediately which results in inflammation. Adreno-corticol
atrophy
b. Allergic Rhinitis, Asthma, MS, Gout, Osteoarthritis (many…)
20. Describe how the menstrual cycle works. Give three examples of Estrogen (and derivatives) uses
in a therapeutic setting . What are three examples of Clinical uses of estrogens?
a. (See notes—gives good description of this process)
b. Estradiol: rapid hepatic elimination
c. Ethinylestradiol (blocked access to glucoronidation because of steric hindrance), much
more widely used
d. Diethyl-Stilbestrol (stilbene derivative, oral contraception)
e. Mestranol
f. Raloxifene (Selective Estrogen Receptor Modifier (SERM)
g. Clinical uses: Replacement therapy, Contraception, Cancer therapy
21. Describe how the male reproductive cycle works. Give 3 examples of Androgens and 2 Antiandrogens
a. (see notes!)
b. Testosterone (muscle growth)
c. Dihydro-testosterone
d. Anabolic Androgens: Nandrolone, Stanozolol (NOT A B-BLOCKER!), DHEA
e. Anti-Androgens=Flutamide, Finasteride
22. Describe the mechanism of Oral contraceptives
a. Either combo of estrogen/progesterone or progesterone alone
i. Combo=Estrogen inhib FSH secretion, progesterone ihib LH secretion, Both
steroids alter endometrium
ii. Prog only: Increases viscosity of mucus (see cycle on how progesterone works in
the female reproductive cycle).
23. Why would someone being treated with hyperlipidemia worry about the effectiveness of an oral
contraceptive?
a. Steroids metab by P450 enzymes
b. Minimal dose of steroid is used to prevent risk of thrombosis
c. Increase in clearance of P450-inducing drugs can result in contraception failure (Statins!)
24. Classify the following endings of drugs based on what they do.
Semide=loop diuretics
Thiazide: thiazide diuretics
Tidine: H2 receptor blocker
Prazole: proton pump inhibitor
Gli/Gly: Second generation sulfonyulureas
Glitazone: Oral hypoglycemic
Statin=lipid lowering drug
Relin=GnRH analog
Drug Review—Lecture 13 and 14
The following are drugs and terms covered in lecture 13 and 14. Fill in all resepective information
regarding the drug/term on the right hand side of the page. This may be useful to study with. Add in as
much detail as you feel necessary (I have provided the basics).
Allergy
Sensitivity to a specific substance (allergen)
Contacted through skin, inhaled, swallowed, injected
Symptoms: Sneezing, Nausea, vomiting, chest pain….
Severe whole-body reaction
Occurs in minutes
Progresses rapidly, can lead to anaphylactic
shock/death
Anaphylaxis
Potential allergens
Latex, nuts, shellfish, eggs, fruits…
Bee stings, etc..
Given to patient with hypersensitivity to
hymenoptera stings
Life threatening situation in systemic grade III and IV
type sensitivity, give Epinephrine to treat
Helpful in anaphylactic shock
Drugs that make up ¾ of all allergic reactions in
patients
Amoxycillin, Cephalosporines, and other antibiotics.
Skin tests (introduce allergens under skin)
To diagnose potential allergens in a patient
Mediators of Allergies
Histamine, cytokines, leukotrienes, PG, T cells/B cells,
monocytes, macrophages
(All aspects of immune system really)
Histamine
Stored in mast cells, basophils, and neurons
Primary stimulant for gastric acid and pepsin secretion
Neurotransmitter
Mediator of immediate hypersensitivity reactions and
acute inflammatory responses
Role in anaphylaxis and ulcer formation
Acts on Vascular system, heart, lungs, GI tract,
Cutaneous nerve endings (see notes for physiological
changes)
Histamine Receptors and Allergy Involvement
H1 receptor present in smooth muscle cells of
airways, GI tract, CV system, endothelial cells.
Responsible for vasodilation, bronchoconstriction,
separation of endothelial cells, pain and itching….
H2 receptor Parietal cells, Vasc smooth muscle cells,
mediate histamine induced gastric acid secretion and
vasodilation
H3 receptor Presynaptic, inhib of histamine synthesis
and release
H4 receptor bone marrow and immune cells, mast cell
chemotaxis
Symptoms of Histamine mediated Allergic
responses
Mild/Cutaneous: erythema, uticariea, and or itching
Moderate: Skin reactions, tachycardia, dysrhythmias,
moderate hypotension, mild respiratory distress
Severe: Hyptotension, ventricular fibrillations, cardiac
arrest, bronchospasm, respiratory arrest
Ethylenediamines
1st generation H1 receptor antagonist, all inverse
agonists--because all H-receptors display baseline
activity, these prevent any binding to receptors and
reduce baseline activity.
Sedating, used as adjunctive in anaphylaxis (H2 antag
and Epinephrine also used), antiallergy, sleep aid,
prevention of motion sickness
Causes dizziness, fatigue, dry mouth, blurred vision,
urinary retention
Ethanolamines
Diphenhydramine
Doxylamine
Clemastine
Alkylamines
Chlorpheniramine
Diphenydramine (Benedryl) treats allergic rhinitis and
skin allergies, penetrates blood brain barrier
Dimenhydrinate (Dramamine): Anti HI and antimuscarinic activity
Doxylamine: Antiallergy, Most potent OTC
sedative/sleep aid
Chlorpheniramine: also antidepressant (inhib serotonin
re-uptake)
Meclizine: antiemetic, less drowsiness
Hydroyzine: antihistamine due to metabolite
Piperazines
Meclizine, Hydroxyzine
Potential drug interactions with 1st generation H1
antagonists
Additive effect when taken with muscarinic Ach
receptor antagonists, Potentiate CNS depressants (ex
alcohol!)
Piperazines
Cetrizine
Piperidines
Loratadine, Fexofenadine
2nd generation H1 receptor antagonists (non-sedating)
Cromolyn (cromoglycate)
Intal
Nasalcrom
Mast cell stabilizers
Only prevent asthma, can not stop attack in progress
Prevents mediator release from mast cells (by
preventing Ca++ influx)
Inhalation/eye drops
Loratadine: does not enter CNS--no drowsiness!
Desloratadine: Longer T ½ (28 hrs), same efficacy as
Loratadine
Fexofenadine: best choice, highly selective H1-receptor
Other derivative of above
Nedocromil (Tilade)
Leukotrienes
Generated by 5-lipoxygenase, converted into LTB4
which is potential mediator of inflammation, and
Cysteinyl-LTs which mediate asthmatic responses
LTB4: Stimulate cytokine and chemokine production
Cys-LTs: contraction of bronchial muscles, peripheral
vasodilation, coronary vasoconstriction
Leukotrienes
Montelukast (Singulair)
Cys-LTs-R antagonists
Zafirlukast (Accolate)
Oral Application
T ½ of Singulair=5 hrs
T ½ of Accolate=10 hrs
Zileuton (Zyflo)
5-Lipoxygenase inhibitor, prevents production of all
LTs. Prevents disease only, not useful in treatment of
attacks
Neurotransmitters in CNS
Norepinephrine
Acetylcholine
Excitory or inhibitory, targeted by MAO inhib
(increased), Increased by tricyclic antidepressants,
increased by amphetamines
Excitory on M1 or N, inhib on M2
Targeted by M inhib (decreased), increased by Achesterase inhib
Excitory, targeted by aniepileptics, ketamine,
phencyclidine (decreased)
Glutamate
Inhibitory, hyperpolariztion
Increased by hypnotics, sedatives, anti-epilieptics
GABA
Inhibitory, decreased by older neuroleptics, increased
by anti-parkinsons and amphtamines
Dopamine
Excitory or Inhib, targeted by MAO inhib, SSRIs,
Tricyclic antidepressants, Hallucinogens (increased by
all)
Serotonin
Anxiety
Types
Panic Disorder
Phobic anxiety
OCD
Generalized anxiety disorder
Post-traumatic stress disorder
Barbituates
Hypnotic effect, enhance GAGA responses, increased
inhib of CNS, block glutamate receptors, anesthetics,
induce P450 system in liver
Long-acting, anticonvulsive
Phenobarbital
Thiopental
Amobarbital, Pentobarbital, Secobarbital
Benzoiazepines
Chlordiazepoxide
Very short acting, lipophilic, redistributed from brain
to fat tissue, [CNS] falls below effective levels, used
for anesthetic (iv)
Selectively activate GABA receptor operated chloride
channels, increase affinity of GABA for receptor
(ligand binding causes conformational change), treat
anxieties, fewer side effects, cause amnesia
First Drug
Strongly anticonvulsive
Diazepam
Lorazepam
Flunitrazepam
Date-rape drug, disinhibiting effect with EtOH leads to
amnesia
Antidepressive properties
Alprazolam
Causes pardocial irratibility (aggressive)
Triazolam
Antidepressants
Tranylcypromine/Phenelzine
Imipramine, Desipramine, Clomipramine,
Amitriptyline, Nortripyline
Many classes of drugs
MAO inhibitors, increase levels of NOR-EP. Serotonin
and dopamine by preventing their metabolism
Severe food interactions (cheese)
Tricyclic antidepressants, increase levels of nor-ep and
serotonin by preventing neuronal reuptake. Side
effect=Sedation
Antidepressants…
SSRIs (selective serotonin reuptake inhibitors)Fluoxetine, Paroxetine, Sertraline, Clotalopram
Increase serotonin, fewer side effects than TCAs, Can
cause aggression
Neuroleptics
Typeical and Atypical drug classes (1st and 2nd
generation)
Phenothiazines (Chlorpromazine,
Triflupromazine, Fluphenazine)
Block dopamine receptors on post synaptic vesicles
Block dopamine receptors on post synaptic vesicles
Butyrophenones (Haloperidol, Trifluperidol,
Spiroperidol)
Classical
Adverse side effects, acute dystonia, akathesia, tardive
dyskinesia, sedation, dry mouth, constipation….
Interaction with alcohol
Ihibit 5-HT, and D2 receptors
Act on limbic system, fewer side effects
Atypical
Clozapine, Olanzpaine, Risperidone, Olanzapine
Parkinson’s Disease
Levodopa (L-Dopa)
Precursor of dopamine, replaces dopamine in system
Carbidopa
LDopa decarboxylase inhibitor, does not cross blood
brain barrier increase the amount of L-Dopa that
reaches the brain
Actions and side effects sim to L-Dopa
Dopamine Agonists (Bromocriptine, Pergolide,
Pramipexole)
Inderect dopamine agonists (Selegiline)
Inhibitor of MAOB, extends t ½ of dopamine,
antidepressant
Epilepsy
Carbamazepine, Tagabin
Enhancement of GABA action
Phenytoin
Inhibition of sodium channels
Ethosuximide, Valproate
Inhib of Ca Channels