Week 1-3

Question 1

What does the Therapeutic Index measure?

Answer 1

Therapeutic Index is a measure of drug safety

Question 2

How do you calculate the therapeutic index?

Answer 2

LD50 = average lethal dose/dose that is lethal in 50% of subjects treated

ED50 = effective dose in 50% of subjects treated

Therapeutic index = ratio of LD50 to ED 50

Question 3

True or false, a high therapeutic index means a drug is safe

Answer 3

True. The highest dose needed to produce effects must be significantly lower than the lowest required to produce death for a medication to be safe. High therapeutic index means safety

Question 4

In terms of drug-drug interactions, there are three general outcomes possible

Answer 4

Potentiative, Inhibitory and creation of a unique response

Question 5

What occurs in a potentiative drug interaction? Provide an example.

Answer 5

Intensification of Effects (Potentiative)

Increased therapeutic effects: can have beneficial potentiative interactions

Increased adverse effects: negative potentiative interactions

Ex. Warfarin and aspirin cause increased risk of bleeding

Question 6

What occurs in an inhibitory drug interaction? Provide an example.

Answer 6

Reduction of Effects (Inhibitory)

Reduced therapeutic effects

Reduced adverse effects: can reduce toxicity.

Ex. Naloxone and morphine

Question 7

What occurs in a drug interaction with creation of a unique response? Provide an example.

Answer 7

Creation of a unique response that does not occur with either drug used alone.

Ex. alcohol and antabuse causing unpleasant responses that do not occur when either is used alone.

Question 8

There are four general mechanisms of drug-drug interactions:

Answer 8

Direct chemical/physical interactions

Pharmacokinetic interactions

Pharmacodynamic interactions

Combined toxicity

Question 9

What is the most common cause of direct chemical/physical drug interactions?

Answer 9

Incompatible IV components being mixed. Can also occur when incompatible drugs are given by other routes.

Question 10

Pharmacokinetic interactions occur when two drugs are taken together that alter the _____, ______, _____, or _____ of the other

Answer 10

Absorption, distribution, metabolism, excretion (ADME)

Question 11

Can you think of an example of a pharmacokinetic interaction related to altered absorption?

Answer 11

Changing pH in stomach can increase the ability of basic drugs to cross membranes and be absorbed

Laxatives can reduce oral drug absorption by decreasing transit time

Drugs that slow peristalsis (morphine, atropine) can prolong transit time and increase absorption of drugs

Drugs that induce vomiting can decrease oral drug absorption

Oral drugs that are not absorbed can absorb other drugs into them and prevent those drugs from being absorbed in the blood. Ex. Cholestyramine

Drugs that reduce blood flow delay absorption

Question 12

Can you think of an example of a pharmacokinetic interaction related to altered distribution?

Answer 12

Competition for protein binding: if two drugs bind same site on plasma albumin then binding of one or both drugs will be reduced, resulting in increased free-drug which could increase drug effects, but if liver/renal function is normal, it usually doesn’t matter as the free drug undergoes elimination

Alteration of extracellular pH changes distribution of drugs. Ex. Making extracellular pH more basic draws acidic drugs out of cells – in aspirin toxicity, giving sodium bicarb helps move aspirin out of the cells and minimizes cell injury

Question 13

Can you think of an example of a pharmacokinetic interaction related to altered metabolism?

Answer 13

One or the most important drug interaction mechanisms

Drugs can increase the metabolism of other drugs by inducing synthesis of hepatic drug-metabolizing enzymes or can decrease metabolism by inhibiting synthesis of these enzymes.

Majority of drug metabolism is catalyzed by cytochrome P450 enzymes – composed of large number of isoenzyme families (CYP1, CYP2, CYP3), further divided into specific forms, 5 of which are responsible for the metabolism of most drugs (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4)

When an inducing agent is taken with another drug, the metabolism of the drug may be increased to the point where drug effect is lost, this would require an increased dose. If the inducing agent is stopped, the dose would then need to be lowered

Inhibition can be harmful or beneficial, can allow achievement of therapeutic drug levels at lower doses, or can lead to toxicity

Question 14

Can you think of an example of a pharmacokinetic interaction related to altered excretion?

Answer 14

Drugs can alter the renal excretion of other drugs in all phases of renal excretion: filtration, reabsorption and active secretion

Glomerular filtration can be decreased by drugs that decrease cardiac output as this decreases renal perfusion and therefore drug excretion

Altering urinary pH can alter drug passive tubular reabsorption

Competition for active tubular secretion can decrease excretion of both agents

Question 15

Pharmacodynamic interactions can be interactions at the same receptor sites or from actions at separate sites. True or false: interactions at the same receptor site can be inhibitory or potentiative

Answer 15

False – these interactions are typically inhibitory as an antagonist drug blocks the access of an agonist drug to its receptor.

This can reduce therapeutic effects or can reduce toxicity

Question 16

Provide an example of a pharmacodynamic interaction with separate receptor sites

Answer 16

Drugs can act at different sites on through difference mechanisms but on the same physiologic processes and thereby alter responses of other drugs. Can be potentiative or inhibitory

Ex. Morphine and diazepam act on different sites but are both CNS depressants, when given together the CNS depressant effects of one reinforces the other

Ex. Two diuretics, spironolactone and hydrochlorothiazide have opposite effects on potassium levels, given together the effects negate each other, resulting in no change to potassium levels

Question 17

If drug A and B are toxic to the same organ then taking them together will cause more injury than if they were not combined. This is called a _______ _______ interaction.

Answer 17

Combined toxicity

Question 18

What are some ways in which food can interact with drugs?

Answer 18

Food can cause decreased rate (which just delays the effects) or extent (which decreases the intensity of peak responses) of drug absorption

Food can also increase absorption in some cases

Question 19

Can you think of any specific food examples that may cause drug interactions?

Answer 19

Grapefruit juice raises drug levels by inhibiting metabolism through the inhibition of cytochrome P450 isoenzymes

Foods containing vitamin K can reduce the efficacy of warfarin

Question 20

What is P-glycoprotein (PGP)

Answer 20

PGP is a transmembrane protein that transports a wide variety of drugs out of cells. Like P450 isoenzymes, PGP experiences induction and inhibition by drugs. Most drugs that induce or inhibit P450 have the same impact on PGP

PGP induction causes: reduced absorption, reduced fetal drug exposure, reduced brain drug exposure, increased drug elimination – all due to increased drug export from cells.

PGP inhibition causes opposite effects

Question 21

Metabolism aka?
What is metabolism?

Answer 21

Biotransformation
= the enzymatic alteration of drug structure

Question 22

WHere does most metabolism of drugs take place?

Answer 22

Liver

Question 23

The P450 system is a hepatic microsomal enzyme system named after cytochrome P450. What’s the deal with this system and cytochrome 450?

Answer 23

responsible for most metabolism in liver

Cytochrome P450 = a group of 12 closely related enzyme families

Three of the cytochrome P450 (CYP) families—designated CYP1, CYP2, and CYP3— metabolize drugs. The other nine families metabolize endogenous compounds (e.g., steroids, fatty acids).

According to internet: “cytochrome P450 (CYP) enzymes are considered the major enzyme family capable of catalyzing oxidative biotransformation (phase 1 metabolism) of most drugs and other lipophilic xenobiotics”
They contain heme.

Question 24

There are 6 possible therapeutic consequences of drug metabolism. The first is accelerated renal excretion of drugs. How does this occur?

Answer 24

most important consequence of drug metabolism!

kidneys cannot excrete highly lipid soluble drugs, so converted into hydrophilic forms during metabolism

Question 25

There are 6 possible therapeutic consequences of drug metabolism. The 2nd is the most common end results of drug metabolism. what is it?

Answer 25

Drug inactivation

Question 26

There are 6 possible therapeutic consequences of drug metabolism. The 3rd is increased therapeutic action of the drug. What is a common example of this?

Answer 26

ex: codeine becomes morphine (so morphine is actually responsible for pain relief from codeine)

Question 27

The 4th therapeutic consequence of drug metabolism has to do with pro-drugs. Describe this.

Answer 27

Activation of prodrugs: a compound that is pharmacologically inactive as administered and then undergoes conversion to its active form through metabolism

Question 28

T/F One function of activation of the pro-drug is that it can allow the drug to more easily pass the BBB

Answer 28

True

Question 29

The 5th possible consequence of drug metabolism is increased toxicity. What is happening here? Example?

Answer 29

Metabolites of the drug are more toxic than the drug itself.

ex - acetaminophen metabolites are what is responsible for hepatotoxicity, not the drug itself

Question 30

The 6th consequence of drug metabolism is decreased toxicity… No question because I don’t know how to formulate one :)
See reverse for summary!

Answer 30

Drug metabolism has six possible consequences of therapeutic significance:
* Accelerated renal excretion of drugs
* Drug inactivation
* Increased therapeutic action
* Activation of prodrugs
* Increased toxicity
* Decreased toxicity

Question 31

The liver doesn’t fully develop in terms of ability to metabolize drugs until what age?

Answer 31

1 year

Question 32

T/F Older adults typically have the same ability to metabolize drugs as younger adults

Answer 32

False - liver function decreases in old age

Question 33

Drugs may be P450 substrates, P450 enzyme inducers, and P450 enzyme inhibitors. What is the general effect of drug metabolism of each of these?

Answer 33

If substrate, drug is metabolized by P450

Inducers increase rate of drug metabolism

Inhibitors dec rate of drug metb

Question 34

T/F A drug can be a P450 substrate AND an inducer

Answer 34

True - can be more than one (inducer, substrate, inhibitor)

Question 35

Describe how P450 enzyme inducers change rate of drug metabolism. Does this increase or decrease drug levels?

Answer 35

Inducers act on liver to inc enzyme synthesis (induction) –> inc rate of drug metb –> plasma drug levels fall (need to adjust dosage to ensure in therapeutic range)

Question 36

T/F P450 enzyme inhibitors risk causing toxicity

Answer 36

True.
Inhibition –> dec metb of drugs –> inc risk of adverse effects/toxicity

Question 37

What is the first pass effect?
How does this affect the drug’s activity?

Answer 37

First Pass Effect: refers to rapid hepatic inactivation of certain oral drugs

Oral meds go GI tract directly to liver via hepatic portal vein before entering system circ

If liver can metabolize all of drug, complete inactivation will occur during first pass & no therapeutic effect will be seen – need to administer these drugs parenterally to bypass first pass effect

Question 38

How does your nutritional status affect your drug metabolism?

Answer 38

cofactors are required for drug-metabolizing enzymes (which you need to get through nutrition)

Question 39

If you take 2 drugs that are metabolized by the same pathway, how might this affect the rate of metabolism?

Answer 39

may compete and decrease rate at which one drug is metabolized

Question 40

What is enterohepatic recirculation? Describe the path of drug movement.

Answer 40

= a repeating cycle in which a drug is transported from the liver into the duodenum (through the bile duct) and then back to the liver (through the portal blood)

Pathway: liver –> excreted in bile into GI tract (duodenum) –> re-absorbed through GI tract –> portal vein back to liver.

Because of enterohepatic recycling, drugs can remain in the body much longer than they otherwise would

Some nitty gritty (probably unnecessary) details:

• process is limited to drugs that have undergone glucuronidation, a process that converts lipid-soluble drugs to water-soluble drugs by binding them to glucuronic acid (then can enter bile)
• In the intestine, some drugs can be hydrolyzed by intestinal β-glucuronidase, an enzyme that breaks the bond between the original drug and the glucuronide moiety, thereby releasing the free drug.
• Because the free drug is more lipid soluble than the glucuronidated form, the free drug can undergo reabsorption across the intestinal wall, followed by transport back to the liver, where the cycle can start again.

Question 41

What are possible ways that drugs are excreted from the body?

Answer 41

Drugs and their metabolites can exit the body in urine, bile, sweat, saliva, breast milk, and expired air.

Question 42

Where does the majority of drug excretion take place?

Answer 42

Kidneys

Question 43

How does renal impairment affect drug response for drugs that are renally excreted?

Answer 43

duration & intensity of drug responses increase

Question 44

What are the 3 steps in renal drug excretion? (just the names, not description)

Answer 44

1) Glomerular filtration
2) Passive Tubular reabsorption
3) Active tubular secretion

Question 45

What is occurring in the glomerular filtration part of renal drug excretion?
What is happening to protein-bound drugs?

Answer 45

Moves drug through the glomerular capillaries into tubular urine

Can’t filter proteins so protein-bound drugs stay in blood

Question 46

Describe what is occurring at the “passive tubular reabsorption” part of renal drug excretion?
How is this different for lipid soluble vs not lipid soluble drugs?

Answer 46

vessels that deliver blood to the glomerulus return to proximity with the renal tubule at a point distal to the glomerulus – at this site, drug concentrations in blood lower than in tubule à concentration gradient drives drugs from lumen back into blood

Because lipid-soluble drugs can readily cross the membranes that compose the tubular and vascular walls, drugs that are lipid soluble undergo passive reabsorption from the tubule back into the blood. In contrast, drugs that are not lipid soluble (ions and polar compounds) remain in the urine to be excreted.

Question 47

Describe what is happening at the “active tubular secretion” part of renal excretion

Answer 47

Active transport systems in tubules pump drugs from blood to tubular urine

Have relatively high capacity & play significant role in excreting certain compounds

Question 48

There are 3 major factors that modify renal drug excretion. The first is pH-dependent ionization. What is the deal with this? How is manipulated to alter rates of drug excretion?

Answer 48

Normally, because ions are not lipid soluble, drugs that are ionized at the pH of tubular urine will remain in the tubule and be excreted (not go back to blood via passive tubular reabsorption)

**can be used to accelerate renal excretion of drugs : Can manipulate urinary pH to promote ionization of drug à decreases passive reabsorption back into blood à hastens excretion

This is used to promote excretion of poisons and meds taken at toxic doses

Question 49

There are 3 major factors that modify renal drug excretion. The 2nd is “Competition for active tubular transport”. What does this mean?

Answer 49

active transport systems of the renal tubules can be envisioned as motor-driven revolving doors that carry drugs from the plasma into the renal tubules. These “revolving doors” can carry only a limited number of drug molecules per unit of time.

Because of competition, if we administer two drugs at the same time and if both drugs use the same transport system, excretion of each will be delayed by the presence of the other.

Question 50

There are 3 major factors that modify renal drug excretion. The last is age. Describe how young/old age affects kidney fx?

Answer 50

Infants kidneys have limited capacity to excrete until 3 months

Older adults have smaller kidneys & fewer nephrons

Vessel changes via atherosclerosis also alter blood flow

Question 51

T/F non-renal routes of drug excretion usually have minimal clinical significant but can be important in certain circumstances

Answer 51

True

Breast milk: Some drugs excreted into milk, exposing infant

Bile is important route of excretion for some drugs – if does not undergo enterohepatic recirculation, will be excreted in feces

Saliva & sweat have little significance

Question 52

Lungs major route for excretion of…?

Answer 52

Lungs major for excretion of volatile anesthetics; EtOh partially excreted this way

Question 53

Which characteristic of drugs will allow them to move more freely into breast milk?

Answer 53

Same passage as any other membrane, so more with lipid-soluble and less with polar, ionized or protein-bound

Question 54

T/F When looking at drug levels, we need to measure the amount of drug present at the site of action. Plasma levels are inadequate for knowing how much drug is really present.

Answer 54

False

Most of time, time course of drug action bears direct relationship to centration of drug in the blood

Can’t regulate amount of drug at site of action so monitor at blood

For most drugs, there is a direct correlation between therapeutic and toxic responses and the amount of drug present in plasma…so we can rely on plasma levels for the most part

Question 55

What is the minimum effective concentration (MEC)?

Answer 55

= the plasma drug level less than which therapeutic effects will not occur

So need the plasma drug level to be above the MEC to have effect

Question 56

What is the “toxic concentration”?

Answer 56

plasma level at which toxic effects begin

Question 57

What is the therapeutic range?

Answer 57

Falls between the MEC and the toxic concentration

There is enough drug present to produce therapeutic responses but not so much that toxicity results – goal of dosing is to keep within this range

Question 58

What is safer: a drug with a wide or narrow therapeutic range?

Answer 58

Wide

Drugs that have a wide therapeutic range can be administered safely with relative ease

Question 59

The therapeutic range is quantified, or measured, by the ________ (another term for similar measurement)

Answer 59

therapeutic index.

Question 60

Of A, D, M, and/or E, which of these processe(s) are primarily determinants of how long drug actions will persist?

Answer 60

Because metabolism and excretion are the processes most responsible for causing plasma drug levels to fall, these processes are the primary determinants of how long drug effects will persist

Question 61

What is a half life?

Answer 61

= the time required for the amount of drug in the body to decrease by 50% (regardless of dose of drug)

Is an index for how rapidly the amount of drug in the body declines

Will determine dosing intervals

Question 62

Does half life apply to ALL drugs?

Answer 62

does NOT apply to the elimination of all drugs.

A few agents, most notably ethanol (alcohol), leave the body at a constant rate, regardless of how much is present

Question 63

What is the plateau drug level?

Answer 63

Administering repeated doses will cause a drug to build up in the body until a plateau (steady level) has been achieved.

When the amount of drug eliminated between doses equals the dose administered, average drug levels will remain constant and plateau will have been reached

Question 64

When a drug is administered repeatedly in the same dose, plateau will be reached in approximately _____ half-lives.

Answer 64

4

Question 65

If you give consistent but larger doses of a drug (say 4 doses of 100mg) instead of 4 smaller doses (25mg), do you reach plateau level faster?

Answer 65

NO
As long as dosage remains constant, the time required to reach plateau is independent of dosage size. Put another way, the time required to reach plateau when giving repeated large doses of a particular drug is identical to the time required to reach plateau when giving repeated small doses of that drug – the HEIGHT of the plateau will be higher with higher doses, but not different in terms of how long it takes to plateau

Question 66

Highest level of drug between doses is the ______ concentration and lowest level is the ______concentration

Answer 66

Peak
Trough

Question 67

Acceptable range of peaks and troughs depends on the drugs ___________

Answer 67

therapeutic range

Question 68

Name 3 techniques for reducing fluctuations in plasma drug levels

Answer 68

1) Administer drugs by continuous infusion

2) administer a depot preparation (releases drug slowly and steadily)

3) reduce both size of each dose and dosing interval (keeping daily dose constant)

Question 69

WHat technique can be used to achieve a plateau level more quickly?

Answer 69

Administer a larger LOADING DOSE

Then can start smaller doses to maintain the plateau = MAINTENANCE DOSES

** This does not mean reaching the plateau for the large loading dose, but rather reaching the plateau for a smaller maintenance dose faster (because of that initial higher dose). If you wanted a plateau for that loading dose, would still need to admin equal doses for period of 4 half lives

Question 70

When drug administration is discontinued, most (94%) of the drug in the body will be eliminated over an interval equal to approximately _____ half-lives

Answer 70

4

Question 71

Define pharmacokinetics

Answer 71

Study of drug movement throughout body

Question 72

Name the four basic pharmacokinetic processes

Answer 72

Absorption, distribution, metabolism, excretion

Question 73

What is absroption?

Answer 73

Drug movement from site of adminstration to the blood

Question 74

What is distribution?

Answer 74

Drugs movement from blood to interstitial space of tissues and from there into cells

Question 75

What is metabolism?

Answer 75

(Biotransformation). Enzymatically mediated alteration of drug structure

Question 76

What is excretion?

Answer 76

Movement of drugs and their metabolites out of body

Question 77

What is elimination?

Answer 77

Combination of metabolism and excretion

Question 78

The rate of absorption determines….

Answer 78

How soon drug effects will begin

Question 79

The amount of absorption determines….

Answer 79

How intense the effects will be

Question 80

What is chemical equivalence

Answer 80

Drugs are chemically equivalent if they contain the same amount of the identical chemical compound (drug)

Question 81

When are drugs considered equal in bioavailability?

Answer 81

When the drug they contain is absorbed at the same rate and to the same extent

Question 82

True or false: Two formulations of the same drug can be chemically equivalent, but differ in bioavailability

Answer 82

True

Question 83

Name some factors that affect drug absorption

Answer 83

Dissolution of drug
Surface area available for absorption (i.e., absorption of orally administered drugs is greater from the small intestine than the stomach bc the intestine has greater SA)
Blood flow (more blood flow= more rapidly absorbed)
Lipid solubility (more lipid soluble is usually absorbed more rapidly)
pH partitioning (faster absorbed if drug has greater tendency to ionize and be absrobed into plasma)

Question 84

What are the 3 main factors affecting drug distribution

Answer 84

Blood flow to tissues, ability of drug to exit the vascular system, and ability of drug to enter cells

Question 85

What kinds of drugs can pass the blood brain barrier

Answer 85

Generally, drugs that are lipid soluble or have a transport system

Question 86

Name the barriers to absorption for IV, IM, SC, and oral routes of administration

Answer 86

IV- none (absorption bypassed)
IM/ SC- capillary wall (easy to pass)
Oral- epithelial lining of GI tract and capillary wall

Question 87

What drugs easily pass through the placenta?

Answer 87

Lipid soluble, non ionized

Question 88

Describe how the absorption pattern differs by route of administration

Answer 88

IV> IM > SC> PO = instantaneous > rapid with water soluble drugs (slow with poorly soluble) > slow and variable

Question 89

Disadvantages of oral route of administration

Answer 89

Variable absorption, inactivation of drugs by gastric acid/ digestive enzymes, possible nausea and vomiting from local irritation, patient must be cooperative

Question 90

What is the most important protein for drug binding in the plasma?

Answer 90

Albumin

Question 91

Why do we care about protein binding?

Answer 91

Protein bound drug cannot leave circulation to have effects on target cell (albumin is too large to leave circulation). They also cannot be metabolized or excreted until the drug protein bond is broken and the drug is free to leave circulation.