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!

  1. Pain killers belong to what type of drug?
  1. Therapeutic
  2. Prophylactic
  3. 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)

  1. 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)

  1. Rank in order of bioavailability (highest to lowest):
  2. Oral
  3. TransdermalIntraveneous>Transdermal>Rectal>Oral
  4. Rectal
  5. Intraveneous
  1. 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.

  1. 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)

  1. 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).
  1. Provide 2 examples of drug-drug interactions. Provide 2 examples of drug-food interactions.
  1. 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

  1. ______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.

  1. 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 threshold; slow inactivation / Plasma membrane of many cells; main Ca++ source for contraction in smooth and cardiac muscle / Dihydropyridines; verapamil; diltiazem
N / Low activation threshold;
slow inactivation / Main Ca++ source for transmitter release by nerve terminals / w-Conotoxin
(snail venom)
T / Low activation threshold;
fast inactivation / Widely distributed; important in cardiac pacemaker and Purkinje cells / Mibefradil; (verapamil; diltiazem)

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:
  7. Pumps (PM Na/Ca exchanger)
  8. PM Ca-ATPase (2 Ca ions transported per ATP molecule hydrolyzed
  9. SR/ER Ca-ATPase
  10. Buffers
  11. Ca Sensors
  12. Annexins (interact with membranes in a Ca dependent manner)
  13. EF-Hand proteins (high affinity Ca binding domain)
  14. Calmodulin
  15. 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 DAG-lipase

Biological functions of PGs:

•Vascular toneRelaxation: PGs E1, E2, F2 and I2

Constriction: PGs F2, TxA2

•Platelet aggregationIncrease: PGs E1, TxA2

Decrease: PGs E2, I2

•Uterus toneIncrease: PGs E1, E2, F1

•Bronchial muscleConstriction: PGFs

Relaxation: PGEs

•Gastric secretionInhibition: PGs E1, E2, I2

•Temperature and painIncrease: 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.
  2. 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.
  1. Explain why Aspirin would be effective if taken once a day, but becomes dangerous if taken more than once a day.
  2. 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).
  1. Explain how LTC4, D4 and E4 mediate an allergic reaction.
  2. 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.
  1. Describe the differences and similarities between classical hormones and cytokines.
  2. 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.
  1. 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)

  1. 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)

  1. Explain the difference between the Muscarinic receptors and Nicotinic receptors.
  2. Muscarinic=G protein-coupled, act on the CNS, gastric mucosa (M1), cardiac (M2), smooth muscle (M3).
  3. Ion channel coupled: muscle type, ganglion type, CNS type
  1. What are the differences in direct parasympathomimetics and indirect parasympathomimetics? Give two examples of both.
  1. Direct=have affinity for M and N receptors and mimic AcCh. Act mostly on the M type receptors with the exception of Nicotine)
  2. Indirect= inhibit the activity of AcChase (enzyme that degrades AcCh) which causes an increase in AcCh
  3. To treat symptoms:
  4. Promote parasympathetic pathways
  5. Block sympathetic pathways
  6. Direct: Muscarinic PSM: Carbachol, Bethanechol, Pilocarpine, Muscarine
  7. Indirect: edrophonium, parathion, carbamates (physosigmine, neostigmine), quaternary alcohols, horny goat weed, organophosphates and nerve gases (irreversible)
  1. 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.
  2. Carbamates: Act as an indirect PSM. Inhibits AcChase, increasing the availability and T ½ of AcCh. Triggers M and N receptors.
  3. Antagonist=parasympatholytics, can be muscarinic or nicotinic receptor blockers. Ex) atropine which prevents hypersecretion of bronchial mucus. It is a muscarinic PSL
  1. Which drug groups can be used to treat acid reflux/ulcers?
  2. Pirenzepine (Muscarinic parasympatholytic)
  1. 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?
  2. : excitatory except in G1 (becomes inhibitory), : inhibitory except in heart (becomes excitatory), 1: cardiac, 2: bronchi, blood vessels
  3. Acetylcholine (all pre and post ganglionic neurons), Norepinephrine (Most sympathetic post ganglionic neurons), Epinephrine (Adrenal Medulla—NO GANGLION)
  4. Describe the process by which termination of norepinephrine can take place.
  5. Reuptake into presynaptic nerve ending
  6. Catechol-O-methyltransferase
  7. Monoamino-oxidase
  8. Presynaptic 2-receptors
  9. 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?
  10. 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)
  11. Ephedrine displaces norepinephrine in storage vesicles, which causes norepinephrine to be released.
  12. Side effects=hypertension, nerve damage, muscle injury…
  1. 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?
  2. 3 different pathways blocked—makes this very effective
  3. Displace norepinephrine, inhibit norepinephrine re-uptake, inhibit degradation by MAO
  4. 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
  1. Why would Clonidine have a sympatholytic effect, eventhough it is actually a sympathomimetic? What does this drug treat?
  2. 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.
  3. Why does Dobutamine have such a strong clinical application for people with impaired cardiac function?
  4. 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.
  5. 1-selective: Mostly found in heart
  6. What are some potential drug targets of antihypertensive drugs?
  7. CNS, ANS (decrease sympathetic tone)
  8. Heart (decrease cardiac output)
  9. Veins (dilate)
  10. Arterioles (dilate)
  11. Kidneys (increase diuresis—secrete more H2O increasing viscosity of blood)
  1. Assign the following drug name endings to the class of drug that they are:
  2. stigmine=AcChase inhib
  3. zoline=1 sympathomimetics
  4. olol=-selective antagonist (sympatholytics)
  5. Exception: LabetAlol: acts on 1 receptors as well
  6. Dipine=L type selective Ca channel blocker

Review/Problem Set Lectures 9-12