Worksheet #1 Bimm 118
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 O-Glucurondiation? 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 GTP-binding 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 |
|L |High activation |Plasma membrane of many cells; main Ca++ |Dihydropyridines; verapamil; diltiazem |
| |threshold; slow |source for contraction in smooth and cardiac | |
| |inactivation |muscle | |
|N |Low activation |Main Ca++ source for transmitter release by |w-Conotoxin |
| |threshold; |nerve terminals |(snail venom) |
| |slow inactivation | | |
|T |Low activation |Widely distributed; important in cardiac |Mibefradil; (verapamil; diltiazem) |
| |threshold; |pacemaker and Purkinje cells | |
| |fast inactivation | | |
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
[pic]
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).
[pic]
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
[pic]
[pic]
Arachidonic Acid Metabolism:
All derivatives of arachadonic acid. Mainly generated through the action of PLA2 and DAG-lipase
Biological functions of PGs:
• Vascular tone Relaxation: PGs E1, E2, F2( and I2
Constriction: PGs F2(, TxA2
• Platelet aggregation Increase: PGs E1, TxA2
Decrease: PGs E2, I2
• Uterus tone Increase: PGs E1, E2, F1(
• Bronchial muscle Constriction: PGFs
Relaxation: PGEs
• Gastric secretion Inhibition: PGs E1, E2, I2
• Temperature and pain 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 Anti-androgens
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).
| |Sensitivity to a specific substance (allergen) |
|Allergy |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 | |
| |Latex, nuts, shellfish, eggs, fruits… |
|Potential allergens |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 |
|Ethanolamines |reduce baseline activity. |
|Diphenhydramine |Sedating, used as adjunctive in anaphylaxis (H2 antag and Epinephrine also used), |
|Doxylamine |antiallergy, sleep aid, prevention of motion sickness |
|Clemastine |Causes dizziness, fatigue, dry mouth, blurred vision, urinary retention |
| | |
| |Diphenydramine (Benedryl) treats allergic rhinitis and skin allergies, penetrates |
| |blood brain barrier |
| |Dimenhydrinate (Dramamine): Anti HI and anti-muscarinic 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 |
|Alkylamines | |
|Chlorpheniramine | |
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| | |
| | |
| | |
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|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 |2nd generation H1 receptor antagonists (non-sedating) |
|Cetrizine | |
|Piperidines |Loratadine: does not enter CNS--no drowsiness! |
|Loratadine, Fexofenadine |Desloratadine: Longer T ½ (28 hrs), same efficacy as Loratadine |
| |Fexofenadine: best choice, highly selective H1-receptor |
|Cromolyn (cromoglycate) |Mast cell stabilizers |
|Intal |Only prevent asthma, can not stop attack in progress |
|Nasalcrom |Prevents mediator release from mast cells (by preventing Ca++ influx) |
| |Inhalation/eye drops |
| | |
| | |
| |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 |
| | |
| |Oral Application |
|Zafirlukast (Accolate) |T ½ of Singulair=5 hrs |
| |T ½ of Accolate=10 hrs |
| | |
| |5-Lipoxygenase inhibitor, prevents production of all LTs. Prevents disease only, |
|Zileuton (Zyflo) |not useful in treatment of attacks |
|Neurotransmitters in CNS | |
| |Excitory or inhibitory, targeted by MAO inhib (increased), Increased by tricyclic |
|Norepinephrine |antidepressants, increased by amphetamines |
| | |
| |Excitory on M1 or N, inhib on M2 |
| |Targeted by M inhib (decreased), increased by Ach-esterase inhib |
| | |
|Acetylcholine |Excitory, targeted by aniepileptics, ketamine, phencyclidine (decreased) |
| | |
| |Inhibitory, hyperpolariztion |
| |Increased by hypnotics, sedatives, anti-epilieptics |
|Glutamate | |
| | |
| |Inhibitory, decreased by older neuroleptics, increased by anti-parkinsons and |
| |amphtamines |
|GABA | |
| | |
| |Excitory or Inhib, targeted by MAO inhib, SSRIs, Tricyclic antidepressants, |
| |Hallucinogens (increased by all) |
|Dopamine | |
| | |
| | |
| | |
|Serotonin | |
| | |
|Anxiety |Panic Disorder |
|Types |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 | |
| |Very short acting, lipophilic, redistributed from brain to fat tissue, [CNS] falls|
| |below effective levels, used for anesthetic (iv) |
|Thiopental | |
| | |
| | |
|Amobarbital, Pentobarbital, Secobarbital | |
|Benzoiazepines |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 |
|Chlordiazepoxide | |
| | |
|Diazepam | |
| |Date-rape drug, disinhibiting effect with EtOH leads to amnesia |
|Lorazepam |Antidepressive properties |
| | |
|Flunitrazepam | |
| |Causes pardocial irratibility (aggressive) |
|Alprazolam | |
| | |
| | |
|Triazolam | |
|Antidepressants |Many classes of drugs |
| | |
|Tranylcypromine/Phenelzine |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 |
|Imipramine, Desipramine, Clomipramine, Amitriptyline, Nortripyline |neuronal reuptake. Side effect=Sedation |
| | |
| | |
| | |
|Antidepressants… | |
| |Increase serotonin, fewer side effects than TCAs, Can cause aggression |
|SSRIs (selective serotonin reuptake inhibitors)-Fluoxetine, Paroxetine, | |
|Sertraline, Clotalopram | |
|Neuroleptics |Typeical and Atypical drug classes (1st and 2nd generation) |
| | |
| |Block dopamine receptors on post synaptic vesicles |
|Phenothiazines (Chlorpromazine, Triflupromazine, Fluphenazine) | |
| | |
| | |
| |Block dopamine receptors on post synaptic vesicles |
|Butyrophenones (Haloperidol, Trifluperidol, Spiroperidol) | |
| | |
| |Adverse side effects, acute dystonia, akathesia, tardive dyskinesia, sedation, dry|
|Classical |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 |
| | |
| | |
| |LDopa decarboxylase inhibitor, does not cross blood brain barrier increase the |
|Carbidopa |amount of L-Dopa that reaches the brain |
| | |
| | |
| |Actions and side effects sim to L-Dopa |
| | |
|Dopamine Agonists (Bromocriptine, Pergolide, Pramipexole) | |
| |Inhibitor of MAOB, extends t ½ of dopamine, antidepressant |
|Inderect dopamine agonists (Selegiline) | |
|Epilepsy | |
| | |
| | |
|Carbamazepine, Tagabin |Enhancement of GABA action |
| | |
| | |
|Phenytoin |Inhibition of sodium channels |
| | |
| | |
|Ethosuximide, Valproate |Inhib of Ca Channels |
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