Pharmacokinetics + Pharmacodynamics

Question 1

Pharmacokinetics is the study of:

Pharmacodynamics is the study of:

Answer 1

PK: study of factors determining the amount of drug at the receptor site (dose-concentration)

PD: study of mechanisms by which drugs produce their biological effects (dose-response)

Question 2

What does knowledge of pharmacokinetics help with?

Answer 2

Helps choose most effective route, dosage and schedule and permits prediction of changes in concentration of a drug with time

Question 3

Match the terms to their definitions:

1) Absorption
2) Distribution
3) Metabolism
4) Excretion

A) elimination of a chemically unchanged drug, or its metabolites, from the body.

B) aka biotransformation. Enzymatic conversion of a chemical entity (drug) into another.

C) movement of drug from site of administration into blood. generally involves crossing a BIOLOGICAL membrane. CRITICAL determinant of how rapidly the effects of a drug will be seen

D) movement of drug through the body and to its SOA generally via vascular system.

Answer 3

Absorption: movement of drug from site of administration into blood. generally involves crossing a BIOLOGICAL membrane. CRITICAL determinant of how rapidly the effects of a drug will be seen

Distribution: movement of drug through the body and to its SOA generally via vascular system.

Metabolism: aka biotransformation. Enzymatic conversion of a chemical entity (drug) into another.

Excretion: elimination of a chemically unchanged drug, or its metabolites, from the body.

*Elimination = the irreversible loss of drug from the body. two processes contribute to drug elimination: metabolism and excretion

Question 4

What are the four factors absorption is dependent on?

Answer 4

1) Chemical and physical properties of the drug (larger + polar drugs have a diff time crossing membranes)

2) Surface area for penetration (greater SA = greater absorption)

3) Route of administration

4) pH at site of absorption (determines if drug will be polar or not)

Question 5

(T/F) Membranes function as a barrier to the free movement of drug in and out of the bloodstream. Ability to cross membrane determines where and how long a drug will be present in the body.

Answer 5

True!

*crossing the membrane determined by polarity + size of drug

Question 6

What are the three ways to cross a membrane?

Answer 6

1) channels and pores
2) transport systems
3) penetration of the membrane

Question 7

Match the ways to cross a membrane to their descriptions:

1) Channels and pores
2) Transport systems
3) Penetration of the membrane

A) MOST COMMON mechanism for absorption (most drugs are too large or lack transport systems). Drug must be lipid soluble to penetrate the lipids.

B) Usually in ION FLOW, may be exploited for absorption of certain drugs. RARE mechanism of drug absorption. Only very small compounds (MW<200Da) can pass.

C) Large protein-mediated movement of drugs across a membrane. Structure-specific/selective (drug is similar to endogenous compounds). Can be passive or active transport.

Answer 7

Channels and pores: Usually in ION FLOW, may be exploited for absorption of certain drugs. RARE mechanism of drug absorption. Only very small compounds (MW<200Da) can pass.

Transport systems: Large protein-mediated movement of drugs across a membrane. Structure-specific/selective (drug is similar to endogenous compounds). Can be passive or active transport.

Penetration of the membrane: MOST COMMON mechanism for absorption (most drugs are too large or lack transport systems). Drug must be lipid soluble to penetrate the lipids.

Question 8

Distinguish passive and active transport and the different types of active transport.

Answer 8

Passive transport: no energy required + drug moves WITH a concentration gradient

Active transport: energy required + drug moves AGAINST a concentration gradient

Primary active transport: ATP-dependent
Secondary active transport: coupled transport down a concentration gradient is used to fuel movement

Question 9

(T/F) Many drugs are weak acids/bases. They exist as both ionized and unionized forms in a ratio that varies according the pH of the surrounding environment.

Answer 9

True!

Uncharged (unionized) is sufficiently soluble in membrane lipids to cross cell membranes.

Ionized (charged) is incapable of crossing membranes.

Question 10

If pH = pKa then A- = HA. This means ____% of the drug is ionized.

Answer 10

50

Question 11

(T/F) The pH at the site of absorption can vary greatly in the esophagus. Major impact on orally administered drugs.

Answer 11

False!

The pH at the site of absorption can vary greatly in the INTESTINE. Major impact on orally administered drugs.

Question 12

HA <–> H+ + A-

BH+ <–> H+ + B

1) If pH < pKa, more _____ or _____

2) If pH > pKa, more _____ or ______

3) In the stomach (pH 1-3), would a weak base (pKa 8) or a weak acid (pKa 3.5) be absorbed more readily?

4) In the intestine (pH 7), would a weak base or a weak acid be absorbed more readily?

Answer 12

HA + BH+

A- or B

1) HA or BH+

2) A- or B

3) Weak base (pH<pKa): BH+, Weak acid (pH<pKA): HA. The acid would be absorbed more readily.

4) Weak base (pH<pKa): BH+, weak acid (pH>pKa): A-: Less of BH+; so weak base would be absorbed more readily (?)

Question 13

What is enteric coating? Why is it used?

Answer 13

Enteric coating is a polymer barrier applied to oral drugs to prevent exposure to the stomach. Surface is stable at low pH but breaks down in more neutral/alkaline environments.

It is used because:
1) The high acidity of the stomach can lead to inactivation of many drugs.
2) Many drugs can also be damaging to the stomach lining.

Question 14

If the pKa of a drug is 7.1 and the pH of the stomach is 2.5, what percent of the drug will be ionized when administered?

Can this drug be taken orally?

Answer 14

0.002% ionized!

The overwhelming majority of the drug is unionized and able to be absorbed in the stomach! Thus, it can be taken orally.

Question 15

What are proteolytic enzymes? How can they be overcome?

Answer 15

Proteolytic enzymes in the digestive system inactivate drugs!

Example: insulin, liraglutide, “peptide drugs”

Emerging approaches such as nanoparticles, permeation enhancement and conjugation may enable use of oral peptide drugs!

Question 16

A route of absorption is topical (local effect).

Describe it. Give examples. What are the barriers to absorption? What are the advantages and disadvantages?

Answer 16

Description: Drug administered externally directly at the site of action.

Examples: ear/eye drops, antibiotic creams (polysporin), sunscreens

Barriers to absorption: no barriers, drug reaches site of action immediately

Advantages: Easiest route. Drug administered = drug at site of action.

Disadvantages: Irritation can occur (formulation is little acidic; hypersensitivity). Limited applicability, SOA must be external.

Question 17

A route of absorption is topical (systemic effect).

Describe it. Give examples.
What are the barriers to absorption?
What is the absorption pattern?
What are the advantages and disadvantages?

Answer 17

Description: drug administered externally, is absorbed through skin and enters bloodstream through dermal vessels.

Examples: nicotine, nitroglycerine, estrogen patches

Barriers to absorption: skin and adventitia around dermal blood vessels (arm vs heel)

Absorption pattern: generally slow + incomplete. best with low dose, low MW, lipid soluble drugs.

Advantages: convenience, sustained release reduces need for repeated dosing

Disadvantages: limited uses (few drugs will cross the skin at sufficient concentrations)

Question 18

Match the three different types of skin absorption to their definitions:

1) Transcellular absorption
2) Intercellular absorption
3) Follicular absorption

A) drug enters via hair follicle. generally for small, non-polar compounds. follicular absorption is usually minimal.

B) drug crosses through cells (gets into the blood with the highest concentration). most common. generally for small, non-polar compounds

C) drug crosses around cells. less selective since drug does not cross cell membrane (minor contributor to drug absorption)

Answer 18

Transcellular absorption: drug crosses through cells (gets into the blood with the highest concentration). most common. generally for small, non-polar compounds

Intercellular absorption: drug crosses around cells. less selective since drug does not cross cell membrane (minor contributor to drug absorption)

Follicular absorption: drug enters via hair follicle. generally for small, non-polar compounds. follicular absorption is usually minimal.

Question 19

(T/F) Entering the bloodstream does NOT mean that a chemical will be active once it does! A drug must be at a certain threshold to achieve its effects.

Answer 19

True!

Question 20

A route of absorption is oral (po).

Describe it. Give examples.
What are the barriers to absorption?
What is the absorption pattern?
What are the advantages and disadvantages?

Answer 20

Description: Drug is swallowed and absorbed through the digestive system.

Examples: acetominophen, ACE inhibitors, statins

Barriers to absorption: Epithelial lining of GI tract. Capillary wall of blood vessels in GI system.

Absorption pattern: Slow + variable

Advantages: painless, east, economical, can be done at home + potential reversibility/arrest

Disadvantages: requires conscious and cooperative patient. potential for inactivation in stomach (acid/proteolytic enzymes). variability in absorption (first-pass effect)

Question 21

A route of absorption is sublingual (SL).

Describe it. Give examples.
What are the barriers to absorption?
What is the absorption pattern?
What are the advantages and disadvantages?

Answer 21

Description: drug is placed beneath the tongue.

Examples: buprenorphine (suboxone), nitroglycerin, and nifedipine

Barriers to absorption: (thin) dermal layer in the tongue (highly vascularized)

Absorption pattern: rapid entry to blood stream

Advantages: rapid absorption, reversible, first pass effect avoided, may be used in unconscious patients

Disadvantages: unpleasant taste, irritation of mucous membrane, drug can be swallowed (altered PK)

Question 22

A route of absorption is intravenous (IV).

Describe it. Give examples.
What are the barriers to absorption?
What is the absorption pattern?
What are the advantages and disadvantages?

Answer 22

Description: Drug is administered by injection directly to vein.

Examples: morphine, anesthetics

Barriers to absorption: none (100% gets absorbed)

Absorption pattern: N/A

Advantages: immediate, bypass first pass, emergency, compatible with unconscious patients, real time titration of dose possible, large volume of drug allowed, diluted irritant can be injected, blood plasma/fluids can be injected in conjunction with drug.

Disadvantages: irreversible (greater risk with dosing calculations), infection?, phlebitis (inflammation of blood vessels), infiltration of surrounding tissues, highly lipid soluble drugs not possible

Question 23

A route of absorption is rectal (PR).

Describe it. Give examples.
What are the barriers to absorption?
What is the absorption pattern?
What are the advantages and disadvantages?

Answer 23

Description: Drug administered rectally. Solid: SUPPOSITORY. Liquid/gas: ENEMA.

Examples: Indomethacin (anti-inflammatory)

Barriers to absorption: drug is absorbed through rectal lining and enters enteric circulation (fairly superficial but not as much as sublingual)

Absorption pattern: slow, although more rapid than oral. Partial “first pass effect”

Advantages: compatible with unconscious patients, avoids nausea + vomiting, cannot be destroyed by stomach enzymes

Disadvantages: rectal, partial first pass effect

Question 24

A route of absorption is subcutaneous (SC).

Describe it. Give examples.
What are the barriers to absorption?
What is the absorption pattern?
What are the advantages and disadvantages?

Answer 24

Description: Drug is administered under the skin

Examples: insulin

Barriers to absorption: capillary walls of dermal vessels (still better than oral)

Absorption pattern: slow

Advantages: absorption is slow + constant. compatible with highly lipid soluble drugs.

Disadvantages: limited volume. local inflammation/abscess formation. absorption dependent upon blood flow to region.

*45˚

Question 25

A route of absorption is Intramuscular (IM). Describe it. Give examples. What are the barriers to absorption? What is the absorption pattern? What are the advantages and disadvantages?

Answer 25

Description: drug injected directly into muscle Examples: vaccines Barriers to absorption: capillary wall of muscle vessels Absorption pattern: generally slow Advantages: absorption is slow + constant. compatible with highly lipid soluble drugs. Disadvantages: limited volume. local inflammation/abscess formation. absorption dependent upon blood flow to region. *90˚

Question 26

A route of absorption is Inhalation Describe it. Give examples. What are the barriers to absorption? What is the absorption pattern? What are the advantages and disadvantages?

Answer 26

Description: drug is taken in during breathing through lung Examples: corticosteroids, nitrous oxide Barriers to absorption: alveolar lining, lung capillary wall (blood vessels most superficial in lungs) Absorption pattern: rapid Advantages: rapid onset of action. certain drugs can be targeted to lung with lower system levels (bronchodilators) Disadvantages: gaseous drugs better, technique can impact degree of drug delivery/absorption

Question 27

Rank the routes of drug administrations displayed below in order, where 1 is the fastest. IM/SC, IV, skin, SL, Inhalation, Ingestion, rectal

Answer 27

1) IV 2) Inhalation 3) SC 4) IM/SC 5) Rectal 6) Ingestion 7) Skin

Question 28

Briefly describe the First Pass Effect.

Answer 28

A rapid inactivation of drug prior to entry into the systemic circulation. Drugs absorbed in GI tract enter the portal circulation. Therefore, they are exposed to the liver (and its metabolizing enzymes) prior to distribution to the rest of the body. It is a major consideration for drugs taken orally. They get metabolized before reach the SOA - PRE-SYSTEMIC METABOLISM! Certain drugs (morphine, nitroglycerine, buprenorphine) are subject to such an extensive first pass effect that they must be given via alternative routes.

Question 29

Describe Bioavailability. What can reduce it?

Answer 29

Bioavailability: fraction of unchanged drug that reaches the systemic circulation. F = AUC dose absorbed/AUC dose administered IV administation F=1! The fraction will be reduced by incomplete absorption and by hepatic metabolism (1st pass effect). Or by factors like food/drug interactions, intestinal motility, efflux transporters etc.

Question 30

For a 70kg male, the IV AUC of drug X from a 200 mg dose is 150 mg.hr/L. The oral AUC from a 200 mg dose is 13.2 mg.hr/L. What is the bioavailability of drug X? What other conclusions can we draw from these data?

Answer 30

F = AUC po dose absorbed / AUC IV dose administered F = 13.2/150 = 0.088 or 8.8% With such a low bioavailability, this drug would be better administered parenterally.

Question 31

The oral bioavailability of drug Y is ~80%. The standard IV dose is 40 mg. What dose would need to be administered ORALLY to achieve the same plasma concentration as the IV dose?

Answer 31

F = dose absorbed/dose administered 0.80 = 40mg/X X = 50 mg

Question 32

Speed of the drug distribution (equilibration with plasma) depends on the nature of the compartment it is distributing to. Differentiate the two compartments.

Answer 32

1) Central compartments: highly perfused tissues, rapid equilibration. rapid clearance upon drug removal. HEART, LIVER, BRAIN, KIDNEY and BLOODSTREAM. 2) Peripheral compartments: organs with less or more variable perfusion. slower clearance upon drug removal. ADIPOSE TISSUE, SKELETAL MUSCLE. *drug enters and leaves rapidly in 1 unlike 2

Question 33

Movement of drug between compartments (distribution) may be rapid or slow. What is the difference between single and multiple compartment distribution?

Answer 33

Single compartment distribution: Drug distribution between compartments is immediate (behave as one). Reductions in plasma concentrations due to metabolism/elimination. Multiple compartment distribution: Drug distribution is slow. More common. Reduction in plasma concentrations first due to distribution to peripheral compartments and then due to elimination. Certain drugs can partition selectively to individual compartments (i.e., lipophilic drugs in adipose tissues). This can impact on the AMOUNT OF DRUG NEEDED and on the CLEARANCE OF A DRUG.

Question 34

What is volume of distribution (Vd)?

Answer 34

Hypothetical volume of liquid required to account for the observed drug concentration initially measured in the body. Vd = amount in body(dose)/plasma concentration Useful term for understanding where drug is being distributed in the body and in calculating experimental doses needed to achieve a given plasma concentration.

Question 35

Can Vd values be above the total water content in body? Why?

Answer 35

Yes. - Drug-protein binding - Compartmental sequestration (lipid soluble drugs in fat tissues)

Question 36

1000mg of Drug O is given to a 79 kg. Immediately after absorption/distribution his plasma concentration is 2mg/L. What is the apparent volume of distribution? What does the Vd suggest about the distribution of this drug?

Answer 36

Vd = amount in body(dose)/plasma concentration Vd = 1000mg/2mg/L = 500L The drug appears to be partitioning out of the plasma and into a separate body compartment. (HIGH Vd: leaves plasma to another compartment. need more drug concentration to remain in the plasma).

Question 37

How do drugs enter/exit the vascular system (capillary beds)?

Answer 37

In most capillary beds, "large" gaps exist between the cells that comprise the capillary wall. Drugs and other molecules can pass fairly easily into and out of the bloodstream through these gaps. Lipid-soluble compounds can also pass directly through cells of the capillary wall.

Question 38

How do drugs exit the vascular system (blood brain barrier)?

Answer 38

TIGHT JUNCTIONS exist between the cells that comprise capillaries in the central nervous system. This serves as a barrier to many drugs. Only drugs that are LIPID SOLUBLE or that have a TRANSPORT SYSTEM can cross the blood-brain barrier to a significant degree.

Question 39

What is the role of the placenta?

Answer 39

Placenta is a multi-layer barrier of cells which serve to BLOCK THE DIFFUSION OF SUBSTANCES FROM THE MATERNAL TO UTERINE CIRCULATIONS. This protects the fetus. However, placental membrane does NOT constitute an absolute barrier to the passage of drugs. SMALL LIPID SOLUBLE drugs are more likely to cross this barrier.

Question 40

Why is a fetus at a greater risk of damage due to drug exposure?

Answer 40

Poorly developed metabolism system + differentiating tissues.

Question 41

________ causes improper development/malformation of an embryo. ____________ is a sedative once used as a treatment for sleeplessness and morning sickness in pregnant women. However it was _________-associated with neuritis, limb abnormalities and other birth defects.

Answer 41

Teratogen Thalidomide; teratogen

Question 42

Binding of drug to proteins may:

Answer 42

1) Facilitate the distribution of drugs (if it normally would sequester) 2) Slow the excretion of a drug (longer retention) 3) Impair therapeutic activity

Question 43

Drugs bind ________ with various blood proteins, most importantly _________. This molecule is a large molecule and always remains within the blood stream. Only _____ drug can reach an extravascular SOA.

Answer 43

REVERSIBLY; Albumin (70% of proteins in the blood) (molecular weight of albumin is 69,000 while most drugs are <500) Free *bound drug can't be distributed or metabolized

Question 44

(T/F) Similar proteins can compete for the same protein binding sites. Amount of albumin and/or binding capacity may be altered in liver and kidney diseases (cancer, heart failure, sepsis, inflammatory diseases). These lead to an altered PK where the amount of free drug at a given dose is increased.

Answer 44

True!

Question 45

The goal of metabolism is to increase _____ and ______ of compounds to easily excrete them. Drugs are mostly metabolized in the ______, but can also be in:

Answer 45

size; polarity liver; GI tract, kidneys, lungs, placenta, skin

Question 46

Describe the two phases of drug metabolism.

Answer 46

Phase I: addition of a reactive group (-OH, -NH2 and -SH). attach a polar group. Reactions: OXIDATION, HYDROXYLATION, and REDUCTION Phase II: conjugation of the reactive group with a HIGHLY CHARGED, water soluble substrate. Reactions: GLUCURONIDATION, ACETYLATION, CONJUGATION with amino acids.

Question 47

What can drug metabolizing enzymes do?

Answer 47

1) Convert pharmacologically active compounds to inactive forms 2) Activate PRODRUGS (e.g, tamoxifen) 3) Increase therapeutic action of some drugs (codeine --> morphone) 4) Usually decrease toxicity. Can increase toxicity occasionally. The conversion of acetaminophen into a hepatotoxic substance is significant in overdose.

Question 48

(T/F) The result of metabolism is a highly charged, +/- inactive, lipid soluble compound that is readily excreted by the kidneys or in bile.

Answer 48

False! The result of metabolism is a highly charged, +/- inactive, WATER soluble compound that is readily excreted by the kidneys or in bile.

Question 49

What re cytochrome P450 enzymes?

Answer 49

A large superfamily of heme-containing enzymes that metabolize drugs and endogenous compounds. Many phase I reactions are catalyzed by members of the CP450 enzymes. Each enzyme family and its subtypes have distinct substrate specificities and catalyze distinct reactions (with some overlap).

Question 50

The drug metabolizing enzymes (CYP 1-3) are found at highest concentration in _______. ___________ is the most common enzyme subtype involved in drug metabolism.

Answer 50

liver CYP 3A4 (60% of all drugs)

Question 51

What are the other phase I enzymes besides CYP450s?

Answer 51

Alcohol dehydrogenase (ethanol) Aldehyde dehydrogenase

Question 52

CYP450s can display polymorphisms. Describe what that means and the different kinds of enzymes there are.

Answer 52

Polymorphism; a trait that demonstrates a different distribution/activity in >1% of the population. PM: poor metabolizer (drug metabolized very slow; levels are high - ADVERSE effects) EM: extensive metabolizer (normal; EXPECTED effects) URM: ultra rapid metabolizer (drug metabolized very fast; levels are low - LACK OF RESPONSE) *sometimes there is IM: intermediate metabolizers, which metabolize at a rate between PM and EM.

Question 53

Briefly answer the following questions regarding CYP 2D6. 1) What does CYP 2D6 metabolize? 2) Does it display polymorphism? If yes, how? 3) What is it required to activate?

Answer 53

1) beta-blockers (heart drugs), tricyclic antidepressants, and antipsychotics 2) Yes it displays polymorphism in the population. Most are EM, 4-10% are PM and 1-2% URM. Ethiopians and north africans have 30% URM! 3) It is required for the activation of codeine to morphine.

Question 54

While poor metabolizers of CYP 2D6 demonstrate __________ ________ to typical doses of codeine, URMs have suffered _________.

Answer 54

Decreased responsiveness; overdoses *PM: most stays as codeine *URM: lots of morphine than expected

Question 55

CYP activity can be INHIBITED. This causes drug accumulation if it is normally ________ by the enzyme. If drug is ________ by the enzyme, it would have reduced levels. CYP activity can be INDUCED. This causes drug accumulation if it is normally ________ by the enzyme. If drug is ________ by the enzyme, it would have reduced levels.

Answer 55

degraded; activated activated; degraded *if a drug is typically degraded by the enzymes, inducers decrease therapeutic levels whereas inhibitors result in accumulation of a drug

Question 56

While CYP1A is induced by ___________, CYP 3A is induced by _________. CYP3A is inhibited by ___________ and _________.

Answer 56

Cigarette smoke; phenytoin Ketoconazole; erythromycin

Question 57

Grapefruit juice can inhibit _______ _______ thereby _______ the amount of drug that reaches the liver and the systemic circulation.

Answer 57

Intestinal CYP3A4 Increasing

Question 58

Ethanol can be metabolized by alcohol dehydrogenase as well as by _________. Chronic ethanol ingestion can ______ levels of the enzyme.

Answer 58

CYP2E1; increase *an alcoholic is at a greater risk of acetaminophen toxicity

Question 59

What are the three special considerations for metabolism?

Answer 59

1) Age: infants (immature liver) and elderly (reduced liver/kidney function) need drug dosage (or choice) adjustments 2) Nutritional status: drug-metabolism requires a number of co-factors. may be absent in malnourished pt ---> compromised drug metabolism. 3) First-pass effect: rapid hepatic inactivation of an oral drug. drug absorbed from GI tract, carried directly to the liver. therapeutic effects lost. drugs with strong first pass effect must be administered parenterally (IV, IM, SQ)

Question 60

What are the 7 ways in which drugs can exit the body?

Answer 60

1) Urine 2) Bile 3) Sweat/skin 4) Saliva 5) Breast milk 6) Expired air 7) Hair

Question 61

________ is the major route of elimination of drugs in the body. It may be of _______ drug or a ________ _________ (more common).

Answer 61

Urine (renal excretion) Unchanged; polar metabolite

Question 62

What are the three steps of Renal Excretion? Describe them.

Answer 62

1) GLOMERULAR FILTRATION: movement of drugs from blood to urinary filtrate. only low MW drugs can be filtered. (since albumin is not filtered, bound drugs are not filtered). 2) PASSIVE TUBULAR REABSORPTION: due to proximity of blood vessels to tubules, lipid soluble drug can move down a concentration gradient back into blood (polar + ionized remain). 3) ACTIVE TUBULAR SECRETION: certain drug transporters can actively pump drugs into urine (P-glycoprotein, organic acid and base transporters)

Question 63

What are the three factors that can modify renal drug excretion? Describe them.

Answer 63

1) pH dependent ionization: as passive tubular reabsorption is determined by lipid solubility, changes in the pH of urine can alter the passive reabsorption of drugs. 2) competition for active tubular transport: active tubular secretion has limited capacity. two drugs can compete; slows down. 3) decreased kidney function; newborns, elderly, and individuals with chronic kidney disease/function may be impaired and renal drug excretion is decreased.

Question 64

Give an example on how one of the factors that can modify renal excretion, pH dependent ionization, be exploited therapeutically.

Answer 64

Aspirin overdose in children: Aspirin is a weak acid. A treatment is to increase urine pH (more basic). This increases urinary ionization of aspirin and decreases reabsorption.

Question 65

Match the different types of excretion to their definitions: 1) Bile/feces 2) Expired air 3) Breast milk 4) Skin 5) Hair A) certain drugs (generally lipid soluble) may be excreted. polar drugs rarely partition to this. nursing infants may be at a risk of exposure to drugs. B) important for elimination of compounds not absorbed in the gut, and for LARGE water soluble compounds. Higher the MW, the greater this excretion. C) small amounts can be excreted via sweat. benzoic acid, salicylic acid, and alcohol. certain drugs can cause mild DERMATITIS when excreted. not a major consideration therapeutically. D) small amounts of drug may be excreted, eg., methamphetamine. not a major consideration therapeutically but has been used forensically. E) common route of excretion for gaseous drugs (anesthetics). less common for soluble drugs.

Answer 65

Bile/feces: important for elimination of compounds not absorbed in the gut, and for LARGE water soluble compounds. Higher the MW, the greater this excretion. Expired air: common route of excretion for gaseous drugs (anesthetics). less common for soluble drugs. Breast milk: certain drugs (generally lipid soluble) may be excreted. polar drugs rarely partition to this. nursing infants may be at a risk of exposure to drugs. Skin: small amounts can be excreted via sweat. benzoic acid, salicylic acid, and alcohol. certain drugs can cause mild DERMATITIS when excreted. not a major consideration therapeutically. Hair: small amounts of drug may be excreted, eg., methamphetamine. not a major consideration therapeutically but has been used forensically.

Question 66

The pH of saliva varies from ____ to ____. _____________ drugs are excreted passively. _______ after taste is the mouth of a patient may be an indication of drug excreted in saliva. Some basic drugs ______ saliva secretion and are responsible for mouth _______. Examples:

Answer 66

5.8; 8.4 Unionized lipid soluble Bitter Inhibit; dryness Examples: caffeine, phenytoin, theophylline *Typically only small amounts of drug are excreted in this fashion, little therapeutic significance.

Question 67

Match the elimination kinetics to their definitions: 1) First order kinetics 2) Zero order kinetics

Answer 67

First order kinetics: Rate of elimination is DEPENDENT upon the concentration of the drug. A constant FRACTION of the dose is eliminated in a given time period. Most drugs. Zero order kinetics: Rate of elimination is INDEPENDENT on the concentration of the drug. A constant AMOUNT of the dose is eliminated in a given time period. E.g., ethanol and aspirin (at high doses). *when drugs are saturated, they follow 0 order kinetics. *half-life is irrelevant in 0 order kinetics

Question 68

Describe drug clearance.

Answer 68

A measure of the removal of drug from the body. It is typically expressed as the volume of plasma from which all drug is removed in a given amount of time (ml/min, L/hr). Clearance = amount of plasma cleared of all drug/unit time. Knowledge of a drug's clearance allows for prediction of rates of elimination.

Question 69

1) Anish is given 1000mg of Drug K. He has a blood volume of 1 L. After 1 hour, 900 mg of drug remains in Anish. What is the clearance? 2) If his clearance rate remains the same (1st order), how much drug will be left after two hours? 3) If the drug was eliminated via 0 order kinetics, then how much drug will be left at 2 hours?

Answer 69

1) Clearance = amount of plasma cleared of all drug/unit time 100 mg of drug was removed in 1 hour. Drug concentration: 1000mg/L Clearance = 100mg/1000mg/L = 0.1L/hr or 100 mL/hr 2) New plasma concentration - 900mg/L. 0.1 L/hr*900 mg/L = 90 mg removed in the second hour. 900 -90 = 810 mg remaining after 2 hours 3) In 0 order kinetics; consistent amount of drug is removed. So, the amount of the drug removed is the same as the first hour, Thus, 800 mg remaining after 2 hours.

Question 70

Briefly answer these questions about drug half-life: 1) What is it? 2) Are drugs with a short half-life administered more or less frequently than drugs with a long half-life? 3) When drug administration is discontinued, how many half lives are required for most of the drug to be eliminated? 4) How do first order kinetics and zero order kinetics half life differ on a drug elimination curve?

Answer 70

1) Time required for the amount of drug in the body to decline by 50% 2) Drugs with a short half-life must be administered more frequently than drugs with a long half-life. 3) When drug administration is discontinued, most of the drug will be eliminated over five half-lives. 1) 50% 2) 25% 3) 12.5% 4) 6.25% 5) 3.125% 4) For first order kinetics, the half life will be the same for any two points on a drug elimination curve. For zero order kinetics, the half life will NOT be the same for two points on a drug elimination curve.

Question 71

Match the following terms to their definitions: 1) Minimum effective concentration (MEC) 2) Therapeutic range 3) Loading dose 4) Maintenance dose 5) Chronic administration 6) Plateau A) Drugs often need repeated dose. This results in drug accumulation. B) Lies between the MEC and the toxic concentration C) Plasma drug level below which therapeutic effects will not occur. D) When amount of drug eliminated (metabolized/excreted) equals the amount administered. E) Smaller dose given after loading dose to maintain drug concentration in the therapeutic range (equivalent amount of drug lost since last administration) F) Large initial dose used to achieve immediate therapeutic effect when time to plateau is too long. = plasma concentration x Vd

Answer 71

Minimum effective concentration (MEC): Plasma drug level below which therapeutic effects will not occur. Therapeutic range: Lies between the MEC and the toxic concentration Loading dose: Large initial dose used to achieve immediate therapeutic effect when time to plateau is too long. = plasma concentration x Vd Maintenance dose: Smaller dose given after loading dose to maintain drug concentration in the therapeutic range (equivalent amount of drug lost since last administration) Chronic administration: Drugs often need repeated dose. This results in drug accumulation. Plateau: When amount of drug eliminated (metabolized/excreted) equals the amount administered. For a consistent dose/interval, this will be ~5 half lives.

Question 72

(T/F) Drugs with a wide therapeutic are relatively easy to use safely. Drugs with a narrow therapeutic range (digoxin) require careful monitoring.

Answer 72

True!

Question 73

1) A patient is sick. She needs a dose of Drug A. She needs to rapidly achieve a plasma concentration of 7.5 ug/L. Given a weight of 80kg, an apparent volume of distribution of 0.5L/kg, a clearance of 0.04L/hr, calculate the loading dose required. 2) The initial dose worked. But in order to ensure that her plasma levels remain within the therapeutic range she will require a maintenance dose. Given a weight of 80kg, an apparent volume of distribution of 0.5L/kg, a clearance of 0.04L/hr, calculate the maintenance dose required to sustain a plasma concentration of 7.5 ug/L.

Answer 73

1) Loading dose = plasma concentration x Vd Loading dose = 7.5 ug/L x [0.5L/kg*80kg) = 300ug 2) Maintenance dose must match the amount cleared in a given period of time. Clearance = 0.04L/hr x 7.5ug/L = 0.3ug/hr Maintenance dose = 0.3ug/hr

Question 74

What is pharmacodynamics?

Answer 74

The study of biochemical and physiologic effects of drugs and the molecular mechanisms by which those effects are produced. The study of what drugs do to the body and how they do it.

Question 75

What are dose-response relationship? What do they determine?

Answer 75

Relationship between dosage and intensity of the response produced. It determines: minimum amount of drug to produce a response. maximum response. how much to increase dosage to produce desired increase in response.

Question 76

What are dose-response curves generally plotted? What are the two characteristics of drugs revealed in dose-response curves?

Answer 76

They are generally plotted as response vs log[dose]. 1) Maximal efficacy: the largest effect that a drug can produce. 2) Relative potency: the amount of drug that must be given to elicit an effect - implies nothing about maximal efficacy; refers to dosage needed to produce effects

Question 77

Match the terms to their definitions: 1) Affinity 2) KD 3) Efficacy A) a measure of the action of a drug once binding has occurred. determines MAXIMAL RESPONSE to a drug. B) a measure of how tightly a drug binds to its receptor - if a drug does not bind tightly, then the action of the drug will be shorter & the chance of binding will also be less. C) equilibrium dissociation constant. the concentration of drug requires for 50% of the receptor binding sites to be occupied. it is also the concentration at which ligand dissociation from the receptor is equal to ligand association with the receptor.

Answer 77

Affinity: a measure of how tightly a drug binds to its receptor - if a drug does not bind tightly, then the action of the drug will be shorter & the chance of binding will also be less. KD: equilibrium dissociation constant. the concentration of drug requires for 50% of the receptor binding sites to be occupied. it is also the concentration at which ligand dissociation from the receptor is equal to ligand association with the receptor. Efficacy: a measure of the action of a drug once binding has occurred. determines MAXIMAL RESPONSE to a drug.

Question 78

What are biased agonists?

Answer 78

When receptor binding leads to multiple, distinct responses (i.e., GPCRs), biased agonists preferentially activate one of those pathways.

Question 79

While a non-competitive antagonists bind _________ to receptors, competitive antagonists bind _________ to receptors. NC _____ the maximal response an agonist can elicit, the impact is not _______ but is _________. C ________ with agonists for receptor binding, if the drugs have equal affinity, the receptor will be occupied by whichever agent is present in the _______ concentration.

Answer 79

irreversibly; reversibly reduce; permanent; long lasting compete; highest

Question 80

What is receptor desensitization? How is it different than down-regulation?

Answer 80

Continuous/repeated exposure to AGONISTS can cause desensitization of receptors. Particularly in GPCRs; reduces the G protein-coupling efficient/alters binding affinity. It is due to phosphorylation. The SHORT-TERM effect is desensitization (tachyphylaxis) Phosphorylation also signals cell to internalize membrane receptor. Through internalization and regulation of receptor gene expression, there is a decrease in the number of receptors. This LONGER-TERM adaptation is called down-regulation.

Question 81

What is receptor supersensitivity? How is it different than up-regulation?

Answer 81

Continuous/repeated exposure to ANTAGONISTS initially can increase response of the receptor. This is called supersensitivity. Chronic exposure to antagonists can increase the number of receptors via up-regulation.

Question 82

What is drug tolerance? What is the difference in PK and PD tolerance?

Answer 82

Drug tolerance: when same dose of drug given repeatedly loses its effect. or when greater doses needed to achieve a previously obtained effect. PD tolerance: due to receptor down-regulation. describes adaptations to chronic drug exposure at the tissue and receptor level PK tolerance: due to accelerated drug elimination. usually from up-regulation of enzymes that metabolize drugs.

Question 83

What is myasthenia gravis?

Answer 83

an autoimmune disorder in which antibodies destroy nicotinic receptors in skeletal muscle, leading to impaired neurotransmission and muscle weakness. *response to drugs also affected by disease states that alter number and function of receptors.

Question 84

Match the terms to their definitions: 1) ED50 2) LD50 3) Therapeutic index A) measure of a drug's safety. Ratio: LD50/ED50. Large; drug is relatively safe, small; drug is relatively unsafe. B) the dose that is required to produce a defined therapeutic response in 50% of the population. "standard/average" dose. frequently the dose selected for initial treatment. C) typically determined using laboratory animals. it is the average lethal dose; the dose that kills 50% of the animals given that dosage.

Answer 84

ED50: the dose that is required to produce a defined therapeutic response in 50% of the population. "standard/average" dose. frequently the dose selected for initial treatment. LD50: typically determined using laboratory animals. it is the average lethal dose; the dose that kills 50% of the animals given that dosage. Therapeutic index: measure of a drug's safety. Ratio: LD50/ED50. Large; drug is relatively safe, small; drug is relatively unsafe.