Pharmacology

Question 1

Preclinical drug testing

Answer 1

In vitro studies to determine a lead compound from biologic products or chemical synthesis, followed by animal testing to determine efficacy, selectivity, and mechanism of drug action as well as safety concerns including dosing, toxicity, and mutagenicity

Question 2

Phase I new drug testing

Answer 2

20 - 100 healthy patients; intended to determine pharmacokinetics in humans, safe & effective dosing, and toxicity

Question 3

Phase II new drug testing

Answer 3

100 - 300 patients with disease; Investigational New Drug (IND) application describes the specific disease (indication); single blind comparison to placebo or established treatment

Question 4

Phase III new drug testing

Answer 4

1,000 - 3,000 patients with disase; double blind, randomized trial to control for placebo effect and observer bias; approval of New Drug Application (NDA), FDA allows sale as Rx or OTC agent approved for specific indications

Question 5

Phase IV new drug testing

Answer 5

Postmarketing surveillance of drug effects under actual conditions of use in a large number of patients; monitors rare & serious side effects

Question 6

Dietary Supplement Regulation

Answer 6

According to the DSHEA Act of 1994, dietary supplements do not need to be tested for safety / efficacy by the FDA; any health claims made on the label must include disclaimer “not evaluated by FDA, not intended to prevent, diagnose, or treat” but burden to show unsafe lies on FDA

Question 7

Generic equivalency

Answer 7

Bioequivalent drug products are pharmaceutical equivalent drug products (same active ingredient, same dosage formulation, same ROA, same strength / concentration) that also display the same biologic effects (rate and extent of absorption into plasma)

Generic product is bioequivalent to brand name if Cmax, Tmax, and AUC are equivalent

It is assumed that, in the absence of other evidence, bioequivalence = therapeutic equivalence

Question 8

Pharmaceutical equivalents vs. Pharmaceutical Alternatives

Answer 8

Pharmaceutical equivalents - same active ingredients, same dosage formulation, same ROA, same strength/concentration

Pharmaceutical alternatives - same therapeutic moiety but different preparation or dosage formulation (oral vs. IV, rapid vs. extended release)

Question 9

Controlled Substance Regulation (Federal & Colorado)

Answer 9

The Controlled Substances Act requires DEA licensing to prescribe controlled substances:

Schedule I - no accepted medical use, high abuse potential, cannot be prescribed
Schedule II - accepted medical use, high abuse potential; Rxs must be hand written in prescriber’s hand writing, cannot be telephoned to pharmacist, cannot be re-filled
Schedule III, IV, and V (in Colorado) may be telephoned to pharmacist and re-filled up to 5 times in 6 months

Question 10

Oral ROA Considerations

Answer 10

Bioavailability (AUCoral / AUCiv) can vary from 0 to 100%

Weak acids are absorbed better in the stomach pH 1 - 2); weak bases are absorbed better in the upper intestine (pH 3 - 6)

Increased GI mobility increases speed of absorption by allowing drug to reach the greater surface area of the small intestine

Question 11

Bioavailability (F)

Answer 11

Defined as the fraction of unchanged drug reaching systemic circulation following administration by any route

Described by the area under the curve (AUC) of a graph of Cp vs. time obtained following a single dose given by any route, compared to the graph following a single dose by IV

F = AUCroute / AUC iv

Generally only a consideration for oral ROA; most other ROAs have bioavailability approaching 100%

Question 12

Volume of Distribution (Vd)

Answer 12

Describes the size of the compartment necessary to account for the total amount of drug in the body if present at the same concentration as in plasma

The greater the tendency for a drug to remain in the plasma, the smaller the value of Vd

Vd = Dose / Cp

Question 13

Phase 1 Metabolism

Answer 13

CYP450 enzymes catalyze oxidation reactions on lipid-soluble molecules to increase solubility

Other reactions: reduction, hydrolysis (mediated by esterases, amidases, etc.)

Mostly occurs within the smooth ER of liver cells

Phase I enzymes are subject to induction / inhibition

Genetic polymorphisms exist; individuals may be ultrarapid metabolizers or poor metabolizers

CYP3A4 participates in the phase I metabolsim of 50% of all commonly used drugs

Question 14

Phase II Metabolism

Answer 14

Mainly conjugation reactions carried out by transferase enzymes, ex: glucuronyl transferase, N-acetyltransferase, glutathione transferase, sulfotransferase

Tends to increase ionization and increase size

Pathways are generally saturable due to limited supply of conjugation reactants

Question 15

Induction of Phase I drug metabolism

Answer 15

Inducers are generally TFs that increase production of CYP enzyme protein; generally takes 48 - 72 hours to see effect

Examples of inducers: Rifampin, ethanol, St. John’s Wort, Tobacco smoke, phenytoin, phenobarbital

Question 16

Enterohepatic Recirculation

Answer 16

Drug and metabolites with MW > 300 may be absorbed into portal circulation, stored in the gallbladder, excreted via the bile duct and delivered to the intestines where it is reabsorbed and returns to the liver; this process reduces drug elimination and prolongs duration of action by keeping the drug in the body but out of the plasma

Question 17

Drug Clearance (CL)

Answer 17

CL is defined as the volume of plasma (Vd) that is completely cleared of drug in a given period of time by all processes

Clearance is proportional to the elimination constant

Hepatic clearance varies with blood flow to the liver and hepatic metabolic activity; renal clearance varies with kidney function, necessitating “renal dosing”

Question 18

Half Life (t 1/2)

Answer 18

The time required to eliminate 1/2 of the drug present in the body, regardless of total amount

Question 19

Elimination constant (Ke)

Answer 19

The fraction of drug leaving the body, per unit time, via all elimination processes

Ke is the slope of the B elimination phase in a graph of ln Cp vs. time

Question 20

First order elimination kinetics

Answer 20

Rate of drug elimination is proportional to the concentration of the drug in the plasma

Virtually all drugs are eliminated by first order elimination kinetics at therapeutic dosage levels

Question 21

Zero order elimination kinetics

Answer 21

The rate of elimination of a drug from the body is independent of the amount of drug in the body; most often occurs due to saturation of hepatic metabolic processes (i.e. Phase II conjugations)

Occurs at therapeutic doses for aspirin, ethanol, and with toxic doses for many hepatically eliminated drugs

Question 22

Dose fluctuation

Answer 22

Depends on the number of drug half-lives within the dosing interval (tau)

Magnitude of fluctuation is given by 2 ^ n where n = number of half-lives in the dosage interval

Question 23

Dose-response curve

Answer 23

Plots the percent of the maximum response possible (e/Emax) on the y-axis vs. dose (D) on the x-axis

Hyperbolic curve is relatively linear at low doses indicating that, below EC50, response is proportional to dose

Curve is level at high doses indicating that dose-response is saturable

Question 24

Drug Potency

Answer 24

The plasma concentration of a drug required to produce 50% of that drug’s individual maximum effect (EC50)

Depends on the affinity (Kd) of receptors for binding the drug

Question 25

Maximal Efficacy / Power

Answer 25

Used to compare the efficacy of different drugs by comparing Emax values; full agonists have an Emax of 100% whereas partial agonists have an Emax < 100%

Question 26

Competitive Reversible Antagonist

Answer 26

A class of pharmacological antagonist; binds reversibly to the active site of the same receptor as the agonist, blocking the agonist from binding and maintaining the receptor in its inactive conformation Reduces apparent agonist affinity for receptor (decrease in EC50) because more drug must be administered in order to see the same effect; dose-response curve shifts to the right, Emax is unchanged Ex: Metoprolol / Propanalol are competitive reversible antagonists of NE at beta 1 adrenergic receptors in the heart --> lowers HR

Question 27

Noncompetitive Irreversible Antagonist

Answer 27

A class of pharmacological antagonist; binds irreversibly or pseudoirreversibly to the receptor active site, removing functional receptors from the system Emax is reduced

Question 28

Noncompetitive Allosteric Antagonist

Answer 28

A class of pharmacological antagonist; binds irreversibly to a different site on the receptor than the agonist, inhibiting the receptor from responding to an agonist Emax is reduced

Question 29

Physiological antagonist

Answer 29

Activates or blocks a different receptor than is bound by the agonist, usually mediating a physiologic response that is opposite to that of the action of the agonist at its receptor Ex: The effect of histamine via histamine receptors to produce constriction of bronchiolar smooth muscle, and the antagonist action of epinephrine via adrenergic receptors to produce bronchiodialation when used in the treatment of anaphylactic shock

Question 30

Chemical antagonist

Answer 30

Binds to the agonist directly, preventing its action Ex: antacid neutralizing stomach acid

Question 31

Quantal dose-response curves

Answer 31

Plotted as the fraction of a population that experiences an all-or-nothing response at each dose of a drug vs. the log of the dose ED50 refers to the dose at which half of the individuals experienced the all-or-nothing effect

Question 32

Therapeutic Index (TI)

Answer 32

The factor by which the dose that is effective in 50% of individuals (ED50) must be increased in order to cause death in 50% of individuals (LD50)

Question 33

Standard Safety Margin (SSM)

Answer 33

The percent by which the dose that is effective in 99% of the population (ED99) must be increased in order to cause death in 1% of the population (LD1) Useful when patient response to a drug varies widely

Question 34

Mechanism of acetaminophen toxicity

Answer 34

Normally, 70 - 80% of Ac is conjugated through Phase II reactions and 5 - 10% proceeds through a phase I oxidation by CYP2E1, producing the chemically reactive Ac* metabolite which is further detoxified via Phase II At toxic doses (> 4g/day), saturation of Phase II pathways shunts more Ac toward Phase I, producing higher levels of Ac* and leading to eventual depletion of cellular glutathione --> hepatotoxicity Treatment: N-acetylcysteine serves as a precursor for glutathione synthesis and also functions as a nucleophile to capture Ac*

Question 35

Effect of alcohol on acetaminophen toxicity

Answer 35

Alcohol induces CYP2E1, causing increased production of Ac*, and also decreases hepatic glutathione, leading to greater hepatotoxicity Chronic alcoholics should not exceed 2g/day

Question 36

Mechanism of methanol / ethylene glycol toxicity

Answer 36

Methanol is metabolized to formic acid, which causes visual disturbances followed by sudden death from respiratory suppression Ethylene glycol is metabolized to oxalic acid, which causes kidney damage from calcium oxalate crystals leading to acute renal failure Treatment: Giving ethanol to a BAC of .100 - ethanol competitively inhibits alcohol dehydrogenase, reducing production of toxic metabolites - or - administration of fomepizole, followed by hemodialysis to remove methanol / ethylene glycol and toxic metabolites; sodium bicarbonate to correct metabolic acidosis

Question 37

Aspirin

Answer 37

Mechanism: Irreversible inhibition of COX1 and COX2 Effects: Analgesic, Anti-pyretic, anti-inflammatory, anti-platelet Side effects: GI, Bleeding, Renal, delayed Labor, Other: Reyes syndrome (contraindicated in children with viral infection), hypersensitivity allergy in 5-10% of asthmatics

Question 38

Mechanisms of therapeutic uses of NSAIDS

Answer 38

Analgesia - inhibition of COX2 at sites of injury Anti-pyresis - inhibition of COX2 in the hypothalamus Anti-inflammatory - inhibition of COX2 at sites of inflammation Anti-thrombogenesis - inhibition of COX1 in platelets

Question 39

Mechanisms of NSAID side effects

Answer 39

GI irritation (ulceration, bleeding, nausea) - inhibition of COX1 in gastric cells Increased bleeding - inhibition of COX1 (TXA2) in platelets Renal failure - inhibition of COX1 and COX2 in kidney cells Delayed labor - inhibition of COX2 in uterine smooth muscle Thrombosis - inhibition of COX2 (PGI2) in vascular endothelial cells

Question 40

tNSAIDS

Answer 40

i.e. Ibuprofen, Naproxen, etc. Mechanism: Reversible inhibition of COX1 and COX2 Effects: Analgesia, anti-pyresis, anti-inflammation Side effects: GI, bleeding, renal, delayed labor

Question 41

Acetaminophen

Answer 41

Mechanism: Inhibition of COX2 in the CNS Effects: Analgesia, anti-pyresis; NO anti-inflammatory or platelet action Side effects: Mild; minimal renal effects, safe in pregnancy >4g/day leads to hepatotoxicity; acute OD treated with N-acetylcysteine

Question 42

Celecoxib

Answer 42

Mechanism - Selective, reversible inhibition of COX2 Effects: Analgesia, anti-pyresis, anti-inflammation Side Effects: Renal failure, increased thrombosis, delayed labor,

Question 43

COX1

Answer 43

Constitutively expressed GI tract: decreases acid production, increases mucous and bicarbonate (cytoprotective) Platelets - Pro-aggregatory (TXA2) Kidneys: - increases renal blood flow, promotion of diuresis Pain

Question 44

COX2

Answer 44

Expression is induced at sites of inflammation by cytokines Hypothalamus - Fever (PGE2) Pain Vascular endothelium - vasodilation and platelet anti-aggregation (PGI2) Inflammation Uterine contraction

Question 45

Mechanism of Aspirin anti-platelet effect

Answer 45

Low dose aspirin is essentially selective for platelet COX1 because it inhibits irreversibly and platelets, which are anucleate, cannot synthesize new COX1 enzyme; TXA2 synthesis is inhibited, reducing clotting The largest concentration of ASA is contained in the presystemic (portal) circulation where it can have a greater effect on circulating platelet COX1 (versus its effect on endothelial cell COX2) and so the anti-platelet effect of COX1 inhibition is amplified relative to the pro-aggregation effect of COX2 inhibition

Question 46

Legally required components of a prescription

Answer 46

Date Prescriber name, address, professional degree, telephone number Patient name, address Drug name, strength, quantity, formulation Dosage regimen, including amount of drug to be taken; time, frequency, and route of administration; duration of therapy Refill information - one year limit on original prescription, regardless of # refills written Prescriber signature, DEA number

Question 47

Factors affecting oral bioavailability

Answer 47

Ability of drug to survive in GI environment Ability of drug to cross GI membranes (lipid solubility, size, % unionized) Efficacy of drug metabolism by gut wall or liver (first pass effect) Drug formulation (extended release vs. liquid)

Question 48

Considerations of rectal ROA

Answer 48

Useful when oral route is precluded by vomiting, unconsciousness, or GI injury/irritation First pass metabolism is less than for oral ROA as approximately 50% of dose will bypass the liver

Question 49

Considerations of sublingual / buccal ROA

Answer 49

Venous drainage from the mouth is to the superior vena cava; therefore less first pass metabolism plus faster onset of action Useful for drugs that are lipid soluble and relatively potent due to the smaller surface area for absorption

Question 50

Considerations of intramuscular ROA

Answer 50

Onset and extend of absorption affected by local blood flow at site of injection but can approach equivalence with IV route Depot forms suspended in oil or other preparations exhibit slower, more sustained absorption

Question 51

Considerations of subcutaneous ROA

Answer 51

Usually provides slower, constant rate of absorption; rate of absorption can be intentionally altered by varying particle size, protein complexation, etc. Only for non-irritating drugs

Question 52

Considerations of inhalation ROA

Answer 52

Systemic effects: Rapid and complete absorption due to large surface area and high blood flow in pulmonary tissue; comparable to IV Local effects: Application of aerosolized particles at site of action in lungs; effect depends on particle size

Question 53

Considerations of Transdermal ROA

Answer 53

Systemic effects: Prolonged drug levels can be achieved for systemic effects; first pass metabolism is avoided Local effects: Via skin or mucous membranes for treating inflammation, infection, etc. Generally minimal systemic absorption. Drug must be potent, able to permeate skin sufficiently, non-irritating

Question 54

Where do tight junctions limit drug absorption?

Answer 54

GI mucosa - limits absorption of drug into blood through oral ROA Blood Brain Barrier - limits distribution of drug from blood into brain Placenta - limits distribution of drug from blood into fetal circulation Renal Tubules - following filtration, limits reabsorption of drug back into the blood, enhancing excretion

Question 55

Clinical significance of ion trapping

Answer 55

Alteration of urinary pH to ion trap weak acids or bases and hasten renal excretion; i.e. alkalinization of urine can trap weak acid aspirin in overdose situations Greater potential to concentrate basic drugs (i.e. opioids) in more acidic breast milk

Question 56

Plasma protein binding

Answer 56

Reduces concentration of active, free drug in circulation Hinders metabolism and rate of excretion; increases half life & prolongs drug action Decreases Vd Decreases ability to enter CNS across BBB Acidic drugs bind primarily to albumin; basic drugs bind primarily to alpha-1-acid glycoprotein

Question 57

Cytochrome P450 independent oxidations

Answer 57

Phase I reactions mediated by enzymes other than CYP450, most often dehydrogenases, oxidases Ex: Monoamine oxidase, important in neurotransmitter metabolism Alcohol dehydrogenase

Question 58

Inhibitors of Phase I metabolism

Answer 58

Inhibitors work by many mechanisms (competitive, non competitive, etc.) but generally take effect as soon as sufficient hepatic concentration is reached Examples of inhibitors: erythromycin, ketoconazole, fluoxetine and other SSRIs, grapefruit juice, omeprazole, HIV protease inhibitors

Question 59

P-Glycoproteins

Answer 59

ATP-fueled active transporters located on intestinal, renal, and hepatic epithelial cells; function to move xenoiotics, including drugs, out of the cell at sites of entry into the body; in the intestine they function to decrease absorption whereas in the liver and kidney they function to enhance elimination Inhibitors of p-glycoproteins increase drug plasma levels Inducers of p-glycoproteins decrease drug plasma levels

Question 60

How are drugs excreted by the kidney?

Answer 60

Glomerular Filtration - drugs smaller than albumin will be filtered at a rate of 120ml/min; glomerular filtration rates are affected by renal blood flow & function Active tubular secretion - drugs are transported directly from blood into urine at a rate of 120-600mL/min

Question 61

HPA Axis

Answer 61

Stress stimulates the release of corticotropin releasing hormone (CRH) in the hypothalamus; CRH stimulates the release of adrenocorticotropic hormone in the hypothalamus which stimulates the production of cortisol and aldosterone in the adrenal gland. Cortisol produced from the adrenal gland negatively regulates the production of both CRH and ACTH in the hypothalamus

Question 62

Metabolic effects of glucocorticoids - Carbohydrates

Answer 62

Stimulates gluconeogenesis, leading to increased blood sugar and subsequent insulin release Can lead to a diabetes-like state

Question 63

Metabolic effects of glucocorticoids - Protein

Answer 63

Decreases protein synthesis, and increases breakdown of protein to glucose (gluconeogenesis) Can result in peripheral muscle wasting

Question 64

Metabolic effects of glucocorticoids - Fat

Answer 64

Increased breakdown of triglycerides into free fatty acids; elevated insulin caused by increased blood sugar stimulates the uptake of free fatty acids into triglycerides in the central body Can lead to centripetal obesity

Question 65

Mineralcorticoid effects of glucocorticoids

Answer 65

Mimic the effects of aldosterone on mineralcorticoid receptors in response to reduced blood flow Increased reabsorption of Na+ and H2O coupled with loss of K+ and H+ can lead to hypertension, edema, hypokalemia, and metabolic alkalosis

Question 66

Cellular & Vascular effects of glucocorticoids

Answer 66

Vascular effects: reduced vasodilation, decreased fluid exudation Cellular effects: Decreased activation and chemotaxis of neutrophils in areas of acute inflammation; decreased activity of monocytes and lymphocytes, decreased angiogenesis and fibrosis at areas of chronic inflammation

Question 67

Glucocorticoid Metabolism

Answer 67

11-keto glucocorticoids (i.e. Cortisone, Prednisone) are prodrugs that must be activated by 11B hydroxysteroid dehydrogenase I (11B-HSD I) in the liver to form active 11-hydroxy glucocorticoids (i.e. Cortisol, Prednisolone) 11-hydroxy glucocorticoids are inactivated in the kidney by 11B-HSD2, which converts them back to 11-keto glucocorticoids

Question 68

Hydrocortisone

Answer 68

11-keto glucocorticoid pro-drug, must be activated to cortisol by 11B-HSDI in the liver; activated upon first pass metabolism when given orally (no topical activity) Drug of choice for replacement therapy, i.e. Addison's Disease Glucocorticoid and mineralcorticoid action

Question 69

Prednisone

Answer 69

11-keto glucocorticoid, must be activated to prednisolone by 11B-HSDI in the liver; activated by first pass metabolism when given orally (no topical action) Most commonly used oral agent for steroid burst therapy

Question 70

Methylprednisolone

Answer 70

Major parenteral (IV) agent for steroid burst therapy Glucocorticoid action only; no mineralcorticoid activity

Question 71

Dexamethasone

Answer 71

Most potent anti-inflammatory agent; no mineralcorticoid action Used when water retention is undesirable, as in cerebral edema

Question 72

Triamcinolone

Answer 72

No mineralcorticoid action; used topically

Question 73

Fludrocortisone

Answer 73

Drug of choice for mineralcorticoid effects

Question 74

Lipid:water partition coefficient

Answer 74

Describes the ratio of concentrations of a compound in a mixture of two immiscible phases at equilibrium Drugs with a high lipid:water partition coefficient are highly lipid soluble