Pharm Exam 1

•A researcher is studying the effects of two drugs, drug X and drug Y. She is trying to measure the potential of each drug to achieve a certain response. The graphs in the images show some of his observations. She observes that when drug X acts on its own, it produces a much higher response compared to drug Y. When drug Y is added to the reaction, the maximum efficacy (Emax) is lower than expected. She decides to add more drug X to increase the Emax, but the efficacy remains low. Which of the following best describes drug Y? •A. antagonist •B. Full agonist •C. Inverse agonist •D. Competitive antagonist •E. Partial agonist

E. Partial agonist -She observes that when drug X acts on its own, it produces a much higher response compared to drug Y.

An experimental drug has an ED50 of 0.9 mg/kg and a TD50 of 90mg/kg. What is the therapeutic index of this drug? •What is ED50? •What is TD50? •What does therapeutic index tell us? •Dont need to know: If the drug comes in 63mg tablets, how many tablets until ED50 for 70kg patient? TD50?

ED50= dose at which 50% of people respond TD50= dose that produces a toxic effect in 50% LD50 = dose that produces lethal effects in 50% of the population Therapeutic index: relative difference between avg toxic dose and avg therapeutic dose TI= TD50/ED50 90 / 0.9 = 100 100: 1 Dont need to know how to do this In 70kg ed50 is 63mg and TD50 is 6300 mg. So 1 tablet for effective 100 tablets for toxicity

Graphic representation of ADME (absorption, distribution, metabolism, excretion) What is the independent variable TESTED ON STEEP PART OF CURVE: WHAT CAUSES IT

Time = independent variable •Note that IV administration causes "instantaneous absorption" so Tmax is 0, while Oral and IM must undergo absorption before Tmax (Upward part of curve). •Green upward arrows depict Tmax - time at which max concentration in blood occurs (IV has "instantaneous" absorption - no absorptive phase since its injected directly into circulation where we measure concentraiton •The steep portion of the IV curve (Orange bracket) is due to simultaneous distribution out of circulation with elimination Downward part of curves (parallel) = elimination -> independent of route of administration.

Uncharged vs charged substances: Which one is trapped? Acid in acidic medium B

Uncharged substances can diffuse out of where they are, charged substances are "trapped" where they are Acids in acidic substances are not charged = free to diffuse (do not pick up proton) Bases in basic environment (pH>pKa): not ionized = free to diffuse Acid in basic medium: Cough up proton, become ionized / charged, cant leave Base in acidic : Take on proton: get trapped in acidic medium

Metabolic Tolerance

Vmax increases due to increases expression of enzyme, Css (concentration at steady state??) falls unless dose increased Ethanol, antieplieptic drugs

Nifedipine (Procardia XL®) is a drug that reduces blood pressure. The metabolism of nifedipine to inactive product is catalyzed by the CYP450 3A4 isoenzyme. What do you expect will happen to blood pressure if a patient suddenly starts drinking grapefruit juice while taking nifedipine? What if a patient with stable BP on nifedipine who has a long history of drinking grapefruit suddenly quits drinking grapefruit juice?

So BP medication is inactived by CYP3A4, and grapefruit juice inhibits CYP3A4 So, drink grapejuice with medication = lowers blood pressure more What happens if you drink grapefruit juice daily, then you go on the medicine, titrating to daily life style, then you stop drinking grapefruit juice = BP goes up

Somapacitan (Sogroya®) Mecasermin (Increlex®)

Somapacitan: Treat Adults with GH deficinecy Adverse Effects: Back or joint pain, Weight gain, anemia, Swelling in arms or legs, Hypertension, Increase in blood creatinine phosphokinase *PAC-ing on the pounds (weight gain) Mecasermin = recombinant human IGF-1 (may be deficient in IGF-1) Adverse Effects: Hypoglycemia (must administer within 20 mins of snack or meal *think mecaloran NOTE: measure IGF instead of GH

•An AIDS patient has been compliant with his antitretroviral therapy (ART) medications to reduce his viral load. His ART drugs are metabolized to inactive drug by CYP3A4. Which graph best represents what you'd expect if the patient started St. John's wort, a 3A4 inducer that causes more 3A4 to be translated and transcribed? (the green arrow indicates point at which St. John's Wort started)? *Always pay attention to axis labels!!

St. johns wort increases activity of CYP3A4 which deactivates the drug More st. johns wort = less medication working Viral load should go down if drug is working CYP induction takes time to increase , so the answer is C. Its not instant Effect of drug goes down, viral load goes up

Continuous IV Infusion and 1st order elimination Steady State

Steady State: rate of drug in = rate of drug out Takes 5 half lives to reach steady state NOTE the distributive phase clearly seen in left graphic

ED50 and Emax

The ED50 is the dose that is effective in 50% of the population. Emax is the maximum response that a drug can elicit. Emax reflects efficacy.

Do i need to know this?

The equation for a first order concentration versus time curve after a single dose of IV drug is: concentration at any time t (Ct) = initial concentration (Cmax or Co) times e to the power of (-elimination rate constant * t) - What time T is Tmax? 0. Is this likely IV route or PO? IV Looking at the graph, what is Cmax, peak or Co? 10mg/L If the dose administered was 100mg, what is the Vd? 100mg/10mg/L = 10L What is the elimination half-life t1/2? Looking at the graph, we went from 10mg/L to 5mg/L in 5hr, then from 5 to 2.5mg/L in 5 hour, so the half-life is 5 hours. What is the elimination rate constant? Kt=0.693, so 0.693/5 = 0.138hr-1 What is clearance? Cl = Kel*Vd = 0.138 hr-1 * 10L = 1.38L/hr. How many hours until 97% of this drug is eliminated from the body? 5 half-lives times 5 hours = 25 hours.

A 78-year-old female was admitted to the hospital. Current medications include: sertraline (base, pKa = 9.5), diazepam (Base, pKa= 3.0), amiodarone (base, pKa = 7.4), theophylline (acid, pKa = 8.8), ibuprofen (acid, pKa = 4.8). Shortly after administration, which drug was most likely concentrated inside the patient's gastric cells(gastric pH appx 2, mucosal cell pH appx 7, blood/extracellular fluid appx 7.4) assuming that the drugs will passively diffuse from lumen of stomach into the gastric cells? A.Amiodarone B.Diazepam C.Ibuprofen D.Sertraline E.Theophylline

Answer: Ibuprofen Remember: - an "acid" is something that can release hydrogen ions and a base is a substance that accepts hydrogen ions -A weak acid will be more nonionized and therefore more lipid soluble when pKa is greater than pH (this fact removed all of the bases as they will be "trapped" in the stomach and move through the GI tract) -The pH of the stomach is < 2 which means our acidic drugs will be mainly non ionized in the gastric lumen and readily penetrate the gastric mucosal cell membranes -Inside the mucosal cells, the pH is about 7 <<<< this is the key difference between our two acids. Theophylline remains nonionized (pKa 8.8) and passes through the cell membranes... Ibuprofen however becomes ionized due to the lower pKa.

•Digoxin is a drug that blocks Na/K ATPase and slows the heart rate. Digoxin immune Fab is an ovine immunoglobulin with specificity for digoxin. The chart at right depicts serum digoxin levels, serum potassium levels, and heart rate before (time = 0) and every 10 minutes after a patient with toxic digoxin levels received a single dose of digoxin immune Fab (blue arrow) . Which best explains these findings?

a.Digoxin had not completed absorptive phase before Dig immune Fab given - if the continued rise in digoxin levels were due to continued absorption, HR would have decreased and K would have increased b.Digoxin had not completed distributive phase before Dig immune Fab given - the rectification of HR and K makes d a better answer... c.Samples were drawn before steady state attained - we only gave one dose, steady state only occurs with repeated dosing at an interval that is < 5 half-lives d.The dig immune fab is working - the lab measures total digoxin levels (both bound and free) - the dig immune Fab is a protein that binds to digoxin - this "pulls" digoxin out of the tissues into the central compartment (the blood which is where we measure it) Notice that serum K and heart rate change - dig is leaving peripheral receptors - only free dig is free to act. Dig immune Fab (like plasma protein binding) reduces the Vd e.The dose of dig immune fab is insufficient - look at the K+ and heart rate !

HPA Axis Summary Cortisol serves as feed back inhibitor for ________ and _______ secretion

a.Hypothalamic secretion of Corticotropin Releasing Hormone stimulates release of Adrenocorticotropic Hormone from pituitary gland. b.Secreted ACTH then act on adrenal (cortex) gland to release Cortisol from Zona fasiculata. c.Cortisol serves as feed back inhibitor for ACTH and CRH secretion

LD1 and ED99 TD50 and ED50 LY

lethal dose to 1% of population to the effective dose to 99% of the population (LD1/ED99) ED50 is the dose required to produce a therapeutic effect in 50% of the population; TD50 is the dose required to produce a toxic effect in 50% of the population; •Therapeutic index •A drug's therapeutic index is the ratio between the TD50/ED50. •A larger number means a safer drug - in this case the TI is 6 •Safety factor •Is the ratio between the TD1/ED99, in this case 2 A drug with a TI<1 is usually not developed and marketed There should never be an overlap between LD1 and ED99!!

Where do we measure drug levels?

measure drug levels in blood/plasma - drug in tissue does not contribute to measured concentration When drug leaves blood stream, there is low concentration in blood Note: in pharmacology: Lumen of gut and urine count as outside the body

What would happen if I gave methadone + buprenorphine? What about methadone + naloxone?

methadone + buprenorphine: Still some opoid effect, just less methadone + naloxone: even less effect

What is pKa? pH> pKa

pKa: 50% of substance/medium ionized pH> pKa = basic pH< pKa = acidic

A 65-year-old woman presents to her primary care doctor with progressively worsening headaches over the last few years. She has recently been diagnosed with diabetes mellitus and started metformin a week ago. She has no other significant past medical history and has never smoked. Her husband also reports that her face has changed over the past few months. An earlier photograph of this patient and her current appearance are shown side by side in the Figure. Which medication would be most appropriate to add to the patient's therapy a. ganirelix b. mecasermin c. pegvisomant d. leuprolide e. somatotropin

peGvIsomANT Acromegaly, diabetes, too much GH

Legend drugs

prescription drugs •Legend drugs - Rx only •Caution: Federal law prohibits dispensing without a prescription" or "Rx only." Legend drugs must be stored and maintained according to law. •Legend Drugs - Rx valid for 1 year from date written unless drug is controlled or "scheduled" by Drug Enforcement Agency due to risk of abuse: requires prescripton

What should be on a prescription

¡Prescriber name, address, phone (preprinted) ¡Patient name ¡Pt address (usually done by pharmacy) ¡Date rx written ¡Name form and strength of drug ¡Quantity to dispense ¡Signatura or "Sig" = directions ¡How much to take, which route, how often to take it (pharmacist usually translates to lay terms) ¡Refills - # times fillable in addition to original ¡Signature of prescriber ¡Indication of supervising physician for midlevel practitioners ¡Prescriber DEA number if controlled (schedule II-V) drug ¡DEA = A or B + 1st initial of last name + 7 digits ¡Tamper proof features are required ¡Most of these things are covered via e-scribing ¡At DCOM, you must print your name beneath your signature ¡

•A 65-year-old female has been receiving intravenous morphine 10mg IV q4 hours (10 mg every 4 hours). She is to be switched to oral morphine. Morphine has an F factor of 0.3 - meaning that only about 30% (1/3) of oral morphine reaches systemic circulation compared to IV. How many mg of morphine should she get orally to achieve the same AUC as IV? *Looking at F factor

•30 mg - only 1/3 of an oral dose gets to circulation -1/3 PO dose = IV dose, so PO dose = 3 x IV dose. It takes 3 times as much via oral route to get to IV AUC levels. Oral dose usually much higher than IV dose

•How many half lives for 97% of a single dose of drug to be eliminated (by first order elimination) from the body? •How many half lives to steady state? •What if it's a drug that undergoes zero-order elimination?

•A: if you do the math, you'll see that it takes 4-5 half-lives to eliminate 94-97% of a drug (100mg/L to 50 to 25 to 12.5 to 6.25 to 3.125) It takes 5 half-lives for 97% SS (many folks think that 94% (4 t1/2) is close enough for therapeutic drug monitoring. We will never ask you to make the decision between 4 or 5 half-lives on the exam!!! Zero order kinetics = indeterminate time to SS for our purposes

Parenteral routes: Subcutaneous, ID, IM

•Absorptive phase delays onset, may limit bioavailability •Irritants may cause tissue damage (cells die)

•The graph at right shows dose response curve for increasing doses of codeine alone (blue) and codeine after drug X. Drug X most likely has what effect? (remember codeine is a prodrug activated by CYP2D6) Competitive inhibition of opiate receptor Induction of CYP2D6 Inhibition of CYP2D6 Partial agonism at opiate receptor

Inhibition of CYP2D6 = no codeine Codeine has to be activated by CYP2D6 into morphine

CYP2D6 and opiates (codeine)

-Divalproex inhibits UGT, which is involved in phase II hydrocodone/hydromorphone metabolism -Hydrocodone is metabolized to the more potent hydromorphone. Opiates cause death by suppressing respiratory drive *dont give hydrocodone to someone taking divalproex

In order for a drug to be an agonist, it must have both: Antagonist has ___________ but not ___________

-In order for a drug to be an agonist, it must have both affinity and activity -Full agonist binds to receptor and changes it to active conformation producing 100% effect -Partial agonist only turns some receptors on -Antagonist has affinity but not activity -inverse agonist turns off constitutively active receptors Curve A = no antagonist. After treatment with a low concentration of antagonist (curve B), the curve is shifted to the right. Maximal responsiveness is preserved, however, because the remaining available receptors are still in excess of the number required. Curve C, = larger concentration of antagonist, the available receptors are no longer "spare"; instead, they are just sufficient to mediate an undiminished max response. Higher concentrations of antagonist (curves D and E) reduce the number of available receptors to the point that maximal response is diminished. The apparent EC50 of the agonist in curves D and E may approximate the Kd that characterizes the binding affinity of the agonist for the receptor.

Zero order elimination vs First order elimination: What happens when you double the dose?

1st order: If you are at steady state and want to double the serum concentration, you just double the dose *Michales Menton 0 order: if you double the dose , you wayyy more than double serum concentration / steady state concentration

Competitive vs Non-competitive antagonists (again) A competitive antagonist changes the ______ but not the _______ A noncompetitive antagonist will not change the _________, but will _______

A competitive antagonist changes the apparent EC50, but can be "outcompeted" to produce 100% Emax A noncompetitive antagonist will not change apparent EC50, but will reduce Emax *Smallest EC50 = most potent Potency: Measure of how much drug it takes to produce have of the max effect: measure of affinity Efficacy: overall effect in the body

What delivers orally administered drug to the liver before the drug can get to systemic circulation?

A: portal vein

Renal Clearance Aspirin is an acidic drug pKa 3.8. What happens to the amount reabsorbed when you alkalinize the urine in the nephron? How does this affect clearance of aspirin? What if you acidified the urine?

Acid, making more urine more alkaline = trapped in urine: less absorbed How does this affect clearance of aspirin? Increased What if you acidified the urine? Clearence goes down Changing the pH of the urine may enhance or reduce elimination of acidic and basic drugs. It depends on how it changes. Remember: Charged molecules don't diffuse readily through the lipid bilayer. The ionized form is "trapped" on one side of the membrane Acid drugs will be un-ionized in an acidi medium pH<pKa of drug because acidic drugs can't donate a proton when there are too many protons around Basic drugs will be un-ionized in an alkaline environment pH> pKa because there aren't protons around Drugs trapped in the urine are considered irreversibly eliminated

Elimination : first order vs zero order

Amount of drug removed/ unit time First order: as concentration decreases, rate of elimination decreases Every time blood circulates, less and less go to liver and kidney because more is getting eliminated Zero order: •At toxic blood concentrations, drugs often undergo zero order kinetics (drug delivery to organ of elimination > Vmax) •Some drugs are at or above Vmax at normal levels: •Aspirin and Ethanol

Elimination half life (T1/2 elim)

Amount of time it takes to eliminate 50% of drug from body First order: amount eliminated (mg/hr) changes but half life stays the same (same fraction) •For drugs that undergo zero order elimination, the mg/hr eliminated stays the same, so there is no true elimination half-life •Our rate of elimination is constant, but the theoretical volume of blood cleared changes Zero-order drugs = greater potential to accumulate with repeated dosing If you double the daily dose of a zero order drug, you more than double the steady state drug level

•The graph depicts the curve after a single 400 mg dose of antibiotic. A 32 year old male with life-threatening infection needs to achieve and maintain immediate therapeutic antibiotic levels, the MIC for the antibiotic is 60mg/L. Which strategy is most appropriate? (answer in notes) a. Indeterminate due to zero order elimination b. Give a 600mg loading dose, follow with a continuous IV infusion of 420mg/hr c. Start a continuous IV infusion of 420mg/hr d. Start a continuous IV infusion of 600mg/hr

B Asking How do I get to my loading dose? B is the only one that is a loading dose This is first order because half life remains constant Dont need to know math: Constant half-life of 1 hour (40mg/L to 20mg/L in an hour, 20mg/L to 10mg/L in one hour). Therefore there are two ways to calculate the loading dose - for first order drugs changes in steady state concentrations are proportional to changes in dose, so we could set up ratio and proportion: X mg dose/ 60 mg/L = 400mg dose / 40 mg/L; X = 600mg. Alternatively we could calculate the Vd (400mg/40mg/L = 10L), then multiply desired Cmax times Vd: 60mg/L x 10L = 600mg. This is how much antibiotic needed to achieve our target serum concentration. Next we'd calculate clearance: clearance = kel*Vd = 0.7/t1/2 * Vd = 0.7/1 hr * 10L = 7L/hr. Our maintenance dose is always in units of amount of drug per time, so if we start with a piece of information that has amount of drug in numerator (concentration), we can't go wrong: 60mg/L x 7L/hr gives us 420mg/hr!

A 24yo male presents with a morbilliform rash on his torso. His medical history is significant for anxiety. He recently began participation in a clinical trial investigating whether an investigational new drug produces a reduction in anxiety as hypothesized. If the drug is undergoing development via the usual process, what phase is the trial? •A. Phase I •B. Phase II •C. Phase III •D. Phase IV •E. Pre-clinical •F. Post-clinical

B •A. Phase I - done in a few (100ish) HEALTHY folks to check pharmacokinetics/dosing •B. Phase II - proof of concept - does the drug work as hypothesized? •C. Phase III - comparing drug to placebo or standard therapy •D. Phase IV - post-marketing surveillance •E. Pre-clinical - animal models •F. Post-clinical - no such thing

Which letter corresponds to each of the following (dose of codeine alone is increased)? *letter can be more than 1 Competitive inhibition of opiate receptor Induction of CYP2D6 Partial agonism at opiate receptor Irreversible/noncompetitive

B Competitive inhibition of opiate receptor A Induction of CYP2D6 B Partial agonism at opiate receptor C is irreversible/noncompetitive (sorry my crude diagram doesn't keep the Km the same)

•A 63-year-old female presents with tremor, insomnia, anxiety and fast heart rate. Her social history is significant for 40-pack-year history of cigarette smoking (cessation "cold turkey" 3 weeks ago) and daily intake of 2 pots of coffee daily x 50 years. What best explains her symptoms? (answer in notes view) a. Gilbert's syndrome b. Downregulation (reversal of induction) of CYP enzymes c. Induction of p-glycoprotein d. Overuse of nicotine replacement

B. Her symptoms are consistent with caffeine excess. Smoking cessation would cause a reversal of the induction of CYP1A2 (over weeks), which would then decrease the deactivation of caffeine. Gilbert's has nothing to do with caffeine or cigarettes and generally manifests as jaundice P-glycoprotein induction would (if it were involved in caffeine disposition) increase efflux of caffeine OUT of the body or brain Overuse of nicotine might produce similar effects, but there are no clues in the stem to suggest that she's using any product, let alone OVER using AND the stem says "cold-turkey" which usually means without any assistance (FYI cold turkey refers to the opiate withdrawal syndrome...)

Caffeine (activated or deactivated) by CYP___ A caffeine-achieving pharmacology professor quits smoking. Which outcome is most likely regarding her caffeine-related effects (smoking induces CYP____ expression, CYP____deactivates caffeine)?

Caffeine deactivated by CYP142 -increase: energy, insomnia, anxiety, tremor Smoking = more CYP1A2 = less caffeine No smoking = less CYP1A2 = More caffeine effect

Prodrug: Codeine Drug Selected Paths Metabolites IMPORTANT POINTS from these EXAMPLES 1.Some drugs undergo multiple routes of elimination, others do not 2.Drugs may be biotransformed into active, inactive, or toxic compounds (the latter process is known as toxification)(acetiminphen in liver) 3.Some drugs are excreted unchanged 4.Some drugs are administered as prodrugs (lacking inherent activity), often designed to protect labile molecules until activation

Codeine Drug: Morphine Selected Path: Conjugation Metabolites: (a)Morphine 6-glucuronide (i/t) Morphine 3-glucuronide

Competitive vs noncompetitive (allosteric) inhibitors

Competitive: Same Vmax, larger Km *Blocks binding Noncompetitive / allosteric : Same affinity, different Vmax *Changes shape of molecule Competitite: you can outcompete it Noncompetitiive/ irreversible : You cant outcompete it

LY Glucose-6-phosphate dehydrogenase deficiency and hemolysis •CC: A 24 year old male comes to the ED due to yellowed sclera fatigue and severe pruritis. •HPI: recently prescribed the highly oxidant drug primaquine to prevent malaria. After taking the med for a week, he developed jaundice from an accumulation of bilirubin •ROS: severe fatigue, yellowed sclera, SOB, upper abdominal pain. •PE: + Jaundice, splenomegaly •Labs: RBC with Heinz bodies, frequent bite cells, diminished RBC count , normocytic, normochromic •Further analysis reveals that he has inherited a glucose-6-phosphate deficiency. Phase IV

Deficient G6PD = RBCs cant protect against oxidative damage Add drug with strong oxidizing potential (or fava beans) = lysis, "bite cells" , Heinz bodies

Some important points: •Enzyme affinity is NOT an attribute of the class of drugs, it may vary by drug •Object drugs that undergo metabolism by a single enzymatic pathway are more susceptible to addition of an inhibitor -Drugs may be metabolized by multiple isoenzymes that can "pick up the slack" in the presence of an inhibitor -When alternate pathways that produce toxic metabolites are induced, bad things can happen... Individual phenotype often plays a role Acetaminophen toxification

Ethanol induces CYP2E1 and is also metabolized by CYP2E1. Ethanol has a greater affinity for CYP2E1 than does acetaminophen If a person with induced 2E1 takes a normal (but on the high end) dose of acetaminophen while there's ethanol currently being metabolized, it's likely that ethanol will outcompete acetaminophen for the 2E1 - even with extra copies. If the person on a sober day takes the same dose of acetaminophen, toxic formation of NAPQI is likely - the extra 2E1 isn't currently busy with ethanol metabolism If the person quits for a few weeks, the induction decreases and NAPQI formation is not longer likely at normal high-end doses...

•The local zoo herpetologist reports to ED with their 3rd crotalid snake bite. They report that they are allergic to the antivenin. When asked about the type of rxn, they report fever, joint pain, and malaise. What evaluation and action of these Sx is most appropriate? •Not true allergy, move forward with antivenin •Type 1 hypersensitivity, alter therapy •Type 2 hypersensitivity, pretreat with antihistamines •Type 3 hypersensitivity, pretreat with steroids •Type 4 hypersensitivity, treat with steroids when sx develop

First, ask what type of allergic reaction they have •Not true allergy, move forward with antivenin - this is a type 3 rxn to soluble antigen (the animal proteins in antivenin) •Type 1 hypersensitivity, alter therapy - type 1 is IgE/histamine mediated •Type 2 hypersensitivity, pretreat with antihistamines - this is where Ab form against tissue/cell, not histamine related •Type 3 hypersensitivity, pretreat with steroids - we need to treat with antivenin, so will dose with steroids to prevent severity of "serum sickness" •Type 4 hypersensitivity, treat with steroids when sx develop - this is cell meadiated delayed hypersensitivity, eg urushiol from poison ivy

Bioavailabiltiy: *usually looking at oral vs IV Factors that affect F factor:

For anything other than IV, F is going to be less than 1 (100%) F Factor: ratio of drug availability by non-IV route vs IV route Factors that affect F: •First pass metabolism •Solubility/ absorbability •Stability of drug •Formulation of drug delivery

GH excess *Usually caused by: Children vs adult 3 drug types to know:

GH excess usually results from a Somatotroph Adenoma and cause Acromegaly in adults and Gigantism in children and adolescents. Somatostatin Analogs: •Octreotide, lanreotide Dopamine D2 Receptor Agonist: Bromocriptine Pegvisomant (Somavert®) (binds GH rceptor, prevents dimerization)

Hypothalamic Hormone: Ant. pit. hormone: Target organ : Primary target organ hormone / mediator GHRH TRH CRH GnRH Dopamine

GHRH: GH TRH: TSH -> to thyroid -> Thyoxine (T4) and Triiodothyronine CRH: ACTH -> Goes to adrenal cortex -> releases cortisol GnRH: FSH and LH -> gonads -> estrogen, progesterone, testosterone Dopamine: Inhibits prolactin

Grapefruit juice vs St. John's Wort

Grapefruit juice: Inhibitor of drugs St. John's Wort = Inducer of lots of stuff

Membrane barriers and access to organs

Hepatic: pretty leaky Blood brain barrier: Tight junctions (no transcellular movement of drugs) *small lipophillic molecules/podocytes can enter brain Renal tubules: Membranes are relatively non-porous and as such only drugs which are lipophilic or non-ionized (i.e., dependent on pH and pKa) can be passively reabsorbed. Things that are polar filter freely

Corticosteroids: Highly __________philic What carries them through blood? Receptor held inactive by: Binds ____________ in nucleus

Highly Lipophilic, transported with corticosteroid binding globulin (CBG) •Free cortisol can enter cell, binds to receptor (R) held in an inactivated form by heat shock protein 90. •Cortisol binds to receptor and destabilizes inactivation complex, allows receptor to dimerize. Complex enters nucleus and binds to Glucocorticoid response element (GRE) (regulates transcription) mRNA transported to cytoplasm

Route with no absorptive phase

IV = no absorptive phase Bolus = rapid injection

•Drug leaves the blood stream (reversibly) and enters extracellular fluid, cells, and tissues •Lipophilic: •Small Molecular Weight: •High Protein Binding: •Hydrophilic: •Large Molecular Weight: If a drug leaves the blood, what happens to its concentration in the blood? After dosing, how/where do we sample to get an estimate of how much drug is in the body?

If a drug leaves the blood, what happens to its concentration in the blood? Goes down in blood After dosing, how/where do we sample to get an estimate of how much drug is in the body? Measure in blood: Distributes widely = low in blood Lipophilic: widely distributed in body Small Molecular Weight: widely distributed High Protein Binding: stays in plasma Hydrophilic: stays in plasma: stays in blood stream Large Molecular Weight: stays in plasma

Growth Hormone

In periphery: JAK STAT a.hypothalamic secretion of growth hormone-releasing hormone (GHRH) or ghrelin stimulates release of growth hormone (GH), while somatostatin inhibits release of GH. b.Secreted GH from anterior pituitary then stimulates the liver to synthesize and secrete insulin-like growth actor 1 (IGF-1), which promotes systemic growth and inhibits GH release from the anterior pituitary gland. If liver not working, no IGF = no feedback inhibition If GH decreased -> IGF decreased = less feedback inhibition *Note: negative feedback doesnt apply to tumors, they dont care

This graph depicts a concentration (on a log scale) versus time curve for a single IV dose of drug (Y axis concentration, X axis is time). Why does the serum concentration drop so rapidly in the part of the carve denoted as "fast phase?"

In this phase the drug is primarily being distributed out of the bloodstream, but there's also some degree of elimination happening. The "slow phase" is mostly elimination from the body.

Indirect Agonists

Increasing release of neurotransmitter (cocaine, amphetamines) Inhibiting degradation or reuptake of transmitter (SSRIs) Blocking degradation of second messenger (e.g., phosphodiesterase inhibition) (caffeine and cAMP

Enteral: Drugs via GI tract: SL (sublingual), buccal (cheek), PR (per rectum)

Inexpensive, non-invasive Bypass harsh GI environment and bypass first pass through liver (50% of PR will bypass) , erratic but fairly rapid onset

•Induction of transporters requires increased transcription and translation of the protein. Will this happen rapidly (with first dose) or over time with repeated dosing?

It often happens over the course of days to weeks; Allosteric activation may occur (and occur rapidly), but it's less common.

First order elimination : It takes _ half-lives to clear 94% of a drug with first-order clearance, and about _ half lives to clear 97% of the drug

It takes 4 half-lives to clear 94% of a drug with first-order clearance, and about 5 half lives to clear 97% of the drug Half life stays the same in first order

Large vs Small volume of distribution

Leaves blood stream and goes into tissues = large volume of distribution Stays in bloodstream = small volume of distribution

Octreotide (SandoSTATIN®) Lanreotide (Somatuline®)

Long acting somatostain analogs Inhibits GH secretion Tx for Somatotroph Adenomas. Adverse Effects: GI disturbances, gallstones, and cardiac conduction abnormalities.

Functional vs. Metabolic Tolerance *looking at alcohol

Metabolic tolerance describes changes in efficiency or capacity to metabolize ethanol resulting in a decrease in the blood alcohol concentration following a given dose of alcohol. Functional tolerance refers to lessened response to alcohol independent of the rate of metabolism of alcohol.

Most severe drug interactions are _________ in nature Hepatic Clearance: high vs low

Most severe drug interaction are kinetic in nature High extraction ratio drugs(high affinity for liver enzymes) (E>0.7) are extensively cleared by the liver - clearance is said to be "Flow-limited". *Oral drugs Drugs with low hepatic extraction ratios (E<0.3) are said to be capacity limited drugs - the rate of clearance (in ml/hr) is determined by number of enzyme sites

4 phases of drug approval Pharmacokinetics vs pharmacodynamics (and which phase are these in)

Phase 1: healthy people *after preclinical testing to establish safety *Designed to determine drug's pharmacokinetics (dosing: what the body does to the drugs) and pharmacodynamics (effect: what the drug does to the body) *metabolism and MOA Phase 2: People have the condition *preliminary assessment of efficacy, short term side effects Phase 3: Clinical trials, double blind-standard control *more info on efficacy, safety, and benefits:risks *Labeling aproved *Doctors can prescribe off label (gabipentin for seizures or nerve pain) Phase 4: Post marketing surveillance *Use of drug in large, diverse population *identify rare/idiosyncratic side effects

Apparent volume of distribution (Vd) Vd = When do you do sample draw: •Imagine that a lecture hall is the body and a small window in the door is the bloodstream - we look in the window to see how many people are in the room. The door is the only way out of the room (the bloodstream is the "door" that delivers drug to the organ of elimination). •If you're all standing right next to the door, we have a large concentration of people in a small volume of distribution. •If you spread out through the room, we have a small concentration by the window in a large volume of distribution of the whole room.

Only sample drug for drug volume Calculate after single IV dose Vd = dose/Cmax (volume = amount of drug/ (amount of drug/volume)) Wait until Distributive phase is complete before sample draw!

Pharmacokinetics (what the body does to the drugs) overview: *kinetics: think of the body being active/ doing stuff Bound vs unbound drugs

Only unbound drug in plasma is free to distribute/ interact with receptor Labs generally measure both bound and unbound Lipid soluble molecule needs protein carrier (albumin) *Malnutrition = low albumin blood is a watery environment, -> fat-soluble drugs would not disperse unless bound to water-soluble carrier proteins. *Only free (unbound) drugs are free to be eliminated from the body.

Overdose of phenobarbital (acid): What do we want to do to the pH to trap it in the urine? Lets say pKa = 6.5 Normal range of urine = 6-8

Overdose of phenobarbital = acid: can give up proton Lets say pKa = 6.5 Normal range of urine = 6-8 If we want to trap phenobarbital in urine, we want to increase pH Its an acid, to trap it we need basic solution Manipulate pH of gut to trap drugs Outside body (= lumen of gut)

Partial vs Full agonists Partial agonists can act like ______________ when combined with full agonists

Partial agonists may precipitate abstinence syndromes (withdrawal) when added to full agonists in dependent patients Partial agonists can act like antagonists when combined with full agonists A: % of receptor occupancy from full agonist ( single concentration) binding to receptors in presence of increasing concentrations of a partial agonist. *full agonist (blue line) and the partial agonist (green line) compete to bind to the same receptor sites, when occupancy by the partial agonist increases, binding of the full agonist decreases. B: When each of the two drugs is used alone and response is measured, occupancy of all the receptors by the partial agonist produces a lower maximal response than full agonist. C: Simultaneous treatment with single concentration of full agonist and increasing concentrations of the partial agonist *Response from single high concentration of the full agonist decreases as increasing concentrations of the partial agonist compete to bind to the receptor with increasing success; at the same time, the portion of the response caused by the partial agonist increases, while the total response—ie, the sum of responses to the two drugs (red line)—gradually decreases, eventually reaching the value produced by partial agonist alone (compare with B).

Hypothalamus and Pituitary Axis Posterior Pit. Releases (2)

Posterior stores/releases ADH (vasopressin) and Oxytocin (made in hypothalamus) Anterior: GPA: hGH, PRL, ACTH Also TSH, LH, FSH *Release stimulated by Hypothalamus Note: Anterior has blood supply: If you cut off blood supply, everything except for prolactin decreases (no negative feedback)

What determines rate in vs rate out Steady State (rate in = rate out) *We dont always want to reach steady state Time to steady state is _____EPENDENT of dose, and _____ENDENT rate of elimination Independent vs dependent for each

Rate of infusion (rate of drug IN) impacts concentration at steady state Rate out determines how long it takes you to achieve steady state (rate in = rate out) Loading dose does not impact amount of time it takes to get to steady state Time to steady state is INDEPENDENT of dose, and DEPENDENT rate of elimination •A loading dose will shorten the time to achieve steady state drug concentration (fill the "bucket"), but not the actual time it takes to reach steady state (still takes 4-5 half lives) -TIME TO SS depends upon elimination rate! •Load patients when critical to rapidly reach minimum effective concentrations

Somatropin (Genotropin®)

Recombinant Human growth hormone (most common treatment for confirmed GH dependent growth delay) Adverse effects: •pseudotumor cerebri •slipped capital femoral epiphysis •Scoliosis •Edema, and Hyperglycemia (Breaks down fat = more glucose )

Prolactin (PRL) Symptoms of Hyperprolactinemia What 2 things elevate PRL

Resembles GH structure Under influence of Dopamine (Prolactin inhibiting hormone) from hypothalamus So, condition that interrupts hypothalamic-pituitary portal system (blood supply) = decreased secretion of most anterior pituitary gland hormones but increased prolactin release. LACTATION •Prolactin-secreting adenomas (Hyperprolactinemia) suppresses hypothalamic-pituitary-gonadal axis (decrease LH, FSH=infertility) and galactorrhea (excessive milk production) Also hyperprolactinemia -> hypogonadism resulting from inhibition of GnRH (gonadotropin-releasing hormone) release. Estrogen and opiates can elevate

An example of polymorphism in Phase II conjugation: UGT Ironotecan and Gilbert's Gilberts syndrome: Can't conjugate bilirubin *drug interactions are common. Some drugs can outcompete bilirubin for a spot on albumin; when this happens, the unconjugated bilirubin displaced from the albumin precipitates in tissues, leading to jaundice. (scleral icterus = yellow eyes)

SN38 accumulates in GI tract = diahrrea When UGT in the epithelial cells of the intestine is defective, the toxic metabolite of irinotecan accumulates and kills the gut epithelium leading to severe diarrhea. In the presence of Gilbert's syndrome you will likely kill the patient with a dose of drug that is not high enough to produce its therapeutic effect: killing cancer cells. There is a routine test for this polymorphism. Irinotecan, aka "I run to the can" Death by diarrhea and/or neutropenia in patients with Gilbert's syndrome, a lack of UGT function

Comprehensive Question: Drug excretion curve

What route of administration most likely? IV - no absorptive phase What t1/2 elimination? 5 hours (from 8ng to 4mg = 5hr, from 4mg to 2mg = 5 hours) What Vd? 100mg / 8mg/L = 12.5 L What clearance? 12.5L (0.7/5 hr) = 1.75 L/hr

Why loading dose and steady state?

Why? To get to a therapeutic level faster! Why do you want to be a therapeutic level faster? So not every drug reaches its therapeutic window immediately after a dose is given (some do). In these instances, we would rather not wait for our patients to have the benefit of drug therapy so we load them to get to a therapeutic level even though the drug is not at steady state. Steady state is the point at which the amount in is roughly equal to the amount out. You must give the doses close enough together to reach steady state concentrations. Do we always want to reach steady state? NO! For meds that are given PRN we don't really care about steady state Steady state matters clinically when we want to maintain a certain concentration of drug in the body for a period of time. A great example is antibiotics, blood pressure meds, and thyroid medications all need to be at steady state. With antibiotics we will stop them after our course of therapy but you can imagine with thyroid and BP meds you don't want the patient going up and down constantly.

What kind of elimination does this drug undergo? Why the sharp decline from 250 to 200?

Zero order. HINT. LOOK AT THE X and Y AXIS... is it a Log graph? Does the half-life change or remain the same? The drop between 250-200 is due to simultaneous distribution and elimination

Competitive, allosteric antagonism, noncompetitive antagonsim, allosteric potentiation

the green curve represents the effect of orthosteric agonist, unmodulated by any antagonist or potentiator. A. Competitive antagonism occurs when the agonist A and antagonist I compete for the same binding site on the receptor. Response curves for the agonist are shifted to the right in a concentration-related manner by the antagonist such that the EC50 for the agonist increases (e.g., L versus L′, L″, and L′″) with the concentration of the antagonist. B. If the antagonist binds to the same site as the agonist but does so irreversibly or pseudoirreversibly (slow dissociation but no covalent bond), it causes a shift of the dose-response curve to the right, with progressive depression of the maximal response as [I] increases. Allosteric effects occur when an allosteric ligand I or P binds to a different site on the receptor to either inhibit (I) the response (panel C. Increasing concentrations of I shift the curves progressively to right and downward.) or potentiate (P) the response (panel D. Increasing concentrations of P shift the curves progressively to left.). This allosteric effect is saturable; inhibition or potentiation reaches a limiting value when the allosteric site is fully occupied.

Volume Distribution (VD) Equation:

the theoretical volume that would be necessary to contain the total amount of an administered drug at the same concentration that it is observed in the blood plasma *what actually happens: when drug leaves bloodstream, concentration falls and volume increases Calculated as dose/ Cmax (dose/measured concentration)

Side effect vs allergy

•An allergy is an adaptive immune response to an antigen •A drug may bind to cellular proteins, and drug + protein = antigen; in this case the drug is a hapten •Allergic reactions may be immediate (anaphylaxis with SOB, hypotension) or delayed (rash, immune-mediated hemolytic anemia, serum sickness) •If patients report an "allergy", make sure you ask what type of reaction (they may report side effect as an allergy) •A side effect is a predictable, dose-related expression of the drug's activity •For example, drowsiness for diphenhydramine (Benadryl®) or decreased histamine action diphenhydramine (Sominex®) •Idiosyncratic reactions are those that we can't explain due to extension of mechanism and are not dose-related •For example, patients deficient in glucose 6 phosphate dehydrogenase will undergo hemolysis with the antimalarial primaquine. Idiosyncratic effects -> rare => discovered in Phase IV post-marketing surveillance. Patient may not know the difference between allergy and side effects Sometimes side effects are good Therepeutic effect is what you intended, side effect is everything else

•Aspirin is a weak acid with pKa 3.5. In the GI tract, where will aspirin be most greatly absorbed via diffusion - in the stomach (pH appx 2) or duodenum (pH 5)?

•Aspirin as an acid will be less ionized in an acidic medium, so absorption will be higher from the stomach

Codeine (activated or deactivated) by CYP___

•Codeine (inactive until morphine is formed) by 2D6 •Codeine itself is not very active

•What is incorrect or what required info is missing in this Rx? •Cannot refill Rx for OTC med •Cannot write Rx for OTC medication •Date Rx written missing •DOB missing •Physician name printed beneath signature missing

•Date Rx written missing Prescription only for 1 year ( or 6 months for certain drugs)

Dependence, addiction, withdrawal

•Dependence - due to up/down regulation of receptors or altered production of second messengers, presence of xenobiotic is required for normal baseline function over time after prolonged exposure Addiction is continued obsessive use of drug in face of serious negative effects on daily functioning Can be dependent without being addicted!

Direct vs Indirect Agonist (LY)

•Direct agonists bind directly to the receptor. For example, phenylephrine is a full agonist, acting like norepinephrine at the alpha-1 receptor •Some drugs produce their effect by increasing levels of endogenous substances. Both of these substances cause actions like norepinephrine: •Caffeine inhibits breakdown of the second messenger cAMP through inhibition of phosphodiesterase (at right) •FYI sildenafil (Viagra) works on a different PDE isoenzyme •Methamphetamine increases release of norepinephrine from vesicular storage sites

Oral (PO) drug route *Most common First pass through: Why is the oral dose of propranolol is more than 10 times that of the IV?

•Drug is exposed to low gastric pH, digestive enzymes, and enters hepatic portal circulation •First pass through liver has a large concentration of drug-altering enzymes - drug is lost on first pass through the liver = "first pass metabolism" Less risk of toxicity, can delay onset, local or systemic depending on drug •High extraction ratio drugs are metabolized before they are absorbed - this is known as first pass metabolism •The oral dose of propranolol is more than 10 times that of the IV. •What is happening? High hepatic extraction ratio

•Propranolol is a substrate of p-glycoprotein, which transports propranolol back into the lumen of the gut. If a patient drinks a large quantity of grapefruit juice, will propranolol blood levels go up or down?

•Grapefruit inhibits the transporter, so propranolol levels will go up (there's more to the grapefruit story, but this is to illustrate the transport interaction)

•Phenobarbital is a weak acid with pKa 7.3. Which will increase the amount of phenobarbital in the urine: changing pH to 8 or changing pH to 6?

•Increasing pH to 8 will allow phenobarbital to donate its proton to become ionized

Fick's 1st law of difusion: *Lipophilicity What are ionized drugs? Talk about their solubility (more or less lipid soluble) We can alter the concentration gradient by increasing blood flow on the ________________ side of the membrane.

•Lipophilicity: Ionized/hydrophilic drugs (molecules carrying a charge) do not readily pass into tissues whose cells have tight junctions (e.g., CNS, testes, placenta) = low diffusivity IONIZED drugs (molecules carrying a charge) are LESS LIPID SOLUBLE! *ionized = trapped We can alter the concentration gradient by increasing blood flow on the interstitial side of the membrane. *increasing absorption by applying heat = vasodilation , decreasing surfce area (this is why drugs absorb through skin of very old and young better -> thinner skin)

Phase I vs II Metabolism/Biotransformation

•Phase I •Add or unmask a reactive functional group/add polarity •Oxidation via CYP450 •Reduction •Phase II •Conjugate reactive group with highly polar moiety (some drugs only undergo phase I whilst others only phase II) *UGT

Parenteral (IV) drug administration *Parenteral just means penetrating, not always IV

•Rapid onset (no liberation or absorption) •100% bioavailability (all drug is initially available - no "F" fraction of bioavailability) *no drug getting lost, all getting to blood

N-Acetylation Phase II Polymorphism SHIP

•Sulfonamides are a class of drugs including a common ABX •Hydralazine is a drug that dilates arterioles to reduce BP •Isoniazid inhibits cell wall synthesis by bacillus that causes TB •Procainamide is a sodium channel blocker used to treat arrhythmias *NAT2 gene polymorphism = slow acetylators = at risk for drug induced lupus, fast acetylators = less likely to have therapeutic effect

Hypo to anterior pituitary to thyroid

•Thyrotropin-releasing hormone (TRH) (synthesized in hypothalmic neurons -> thyroid stimulating hormone (TSH) (delivered in portal blood to anterior pituitary to stimulate TSH) -> delivered to thyroid, stimulates secretion of thyroid hormones

Functional Tolerance Due to change in

•Tolerance means that a higher dose of drug is required to produce the same response over time. Due to change in receptor sensitivity •Receptor down or upregulation •Depletion of second messengers Lost potency = shift right

(ionized vs unionized) drugs generally pass more readily through nonfenestrated membranes ___________ (acidic vs alkaline) drugs will be un-ionized in an acidic medium (pH_pKa of drug) __________ (acidic vs alkaline) drugs will be ionized in acidic medium (pH _ pKa) __________ (acidic vs alkaline) drugs will be un-ionized in an alkaline environment (pH_pKa) __________ (acidic vs alkaline) will be ionized in alkaline environment (pH_pKa)

•Un-ionized drugs generally pass more readily through nonfenestrated membranes (either on the way into the body, on the way around the body, or on the way out of the body) •Acid drugs will be un-ionized in an acidic medium (pH<pKa of drug) because acid drugs can't donate a proton when there's too many protons around - free to leave •Alkaline drugs will be ionized in acidic medium (pH < pKa), because these drugs will pick up a proton to carry a charge "trapped" •Alkaline (basic) drugs will be un-ionized in an alkaline environment (pH>pKa) because there aren't any protons around (free to leave) •Acid drugs will be ionized in alkaline environment (pH>pKa) because they can readily donate their proton (trapped)

Loading Dose (mg/ mg per liter)

•Vd for drugs often average in population samples-> used to calculate the dose needed to "load" the body to achieve a target Cmax = "loading dose" - used when we want to hit target concentration quickly - for example to get the drug concentration above the MIC (minimum inhibitory concentration) to treat infection. •Life threatening condition

•Which is zero order, which is first order? •With repeated dosing how long will it take to achieve 97% of SS (for the 1st order drug)? •If the Vd for this 1st order drug is 10L, how many mg do we need to give to achieve a Cmax 40mg/L

•Which is zero order, which is first order? •The t1/2 of top graph changes with time = zero order •With repeated dosing how long will it take to achieve 97% of SS for 1st order drug? •5 half-lives •If the Vd for this 1st order drug is 10L, how many mg do we need to give to achieve a Cmax of 40mg/L Cmax (mg/L) = LD mg/Vd L 40mg/L = X mg/10L X=400mg

DEA Controlled Substances What class can not be refilled

•restricted by the DEA, must have DEA number written on Rx •Schedule I - Cannot be prescribed for medical purpose in US (but may be valid elsewhere, eg heroin) •Schedule II (or C-II)(cocaine)(oxycontin) •Can not be refilled •Can write multiple Rx, date with correct date and write "do not fill before" •Schedule III (C-III) and IV- up to 5 refills in 6 months (1 original + 4)