Week 1: Pharmacokinetics I

Question 1

What is pharmacokinetics?

Answer 1

The study of drug movement throughout the body

Question 2

How can pharmacokinetics be summed up? How is it different than pharmacodynamics?

Answer 2

(L)ADME:

Liberation (often ignored)

Absorption

Distribution

Metabolism

Excretion

Pharmacodynamids involves what drugs DO to the body

Question 3

What is liberation and what is it dependent on? What are the different formulations?

Answer 3

The release of a drug from it’s closed form (esp. important for oral medication)

Depends on the way the drug is packaged and what excipients (pharmacologically inactive ingredients) are present.

Immediate and modified (/extended/continuous) release formulations exist.

Question 4

What are C_max and t_max? What is the difference in t_max for immediate and delayed release drugs?

Answer 4

C_max is the maximum plasma concentration of a drug

t_max is the time required to release the maximum concentration of drug (see graphs). t_max is much lower for immediate release drugs compared to delayed release, usually because of excipient factors

Question 5

What is the difference between delayed relase drug formulations and extended/controlled release drug formulations? Why shouldn’t we crush controlled release formulations?

Answer 5

Delayed release formulations have a peak-shaped curve, but take longer to release than immediate release formulations (aka a higher t_max)

Controlled release formulations have a plateau-shaped curve, and maintain a high concentration in the body for a long period of time (see graph). The packaging of these drugs is what allows the controlled release, so crushing them disrupts the packaging and allows for much higher, dangerous concentrations to develop in the body.

Question 6

What is an enteric coating? What is it useful for?

Answer 6

Enteric coating ensures that a drug can pass through the stomach, for example, if the drug is unstable at an acidic pH and active at a basic pH. This allows it to reach the intestine without being dissolved.

Question 7

What are the steps taken for a drug to reach the central compartment?

Answer 7

A drug is given in a dose, then liberated and finally absorbed into the central compartment, which is commonly referred to, in general, as blood

Question 8

What is the central compartment and how does it mediate drug interactions?

Answer 8

The central compartment is the bood, and it can contain free drug, protein-bound drug, and can allow the drug to be:

1) moved to the therapeutic site of actoin
2) Bound and freed within tissue reservoirs
3) moved to an unwanted site of action
4) excreted
5) biotransformed into metabolites and excreted

Question 9

What are the major routes of administration and their first “stops” afterwards? What is the second “stop” common to all drugs?

Answer 9

“Old Pete Four I’s”

Oral or rectal: gut

Percutaneous: skin

Intravenous: plasma

Intramuscular: muscle

Intrathecal: CSF

Inhalation: lung

All of these eventually deliver the drug to blood plasma

Question 10

What are the main ways we excrete drugs?

Answer 10

Urine, feces, exhalation, sweat, and milk (in mothers)

Question 11

What are some examples of maternal drug interactions and the issues they cause?

Answer 11

Anti-seizure medicine, valproic acid, can cross the placenta and acts as a very potent teratogen

ACE inhibitors can cause kidney malformation in the fetus

Question 12

What is oral bioavailability, and how is it calculated?

Answer 12

F (oral bioavailability) = quant. of drug reaching system. circ.

quant. of drug delivered

F differs with the method of administration, with…

intravenous F = 1 > subq = intramuscular > oral ingestion

Question 13

What is the absorption pattern of intravenous administration of a drug?

Answer 13

Absorption is circumvented so there are potentially immediate effects. This is suitable for large volumes, irritating substances, or complex mixtures when diluted.

Question 14

What is the absorption pattern of subcutaneous and intramuscular drug administration?

Answer 14

Prompt from aqueous solution, slow and sustained from repository preparations

Question 15

What is the absorption pattern of orally ingested drugs? What is their bioavailability like? What are it’s upsides and downsides?

Answer 15

Variable, and depends on many factors. The bioavailability of orally ingested drugs is generally low.

The upside is that orally delivered drugs are more convenient and economical, and are usually safer.

The downside is that taking these drugs requires patient compliance, and that bioavailability is potentially erratic and incomplete.

Question 16

What are some of the limitations of IV drug delivery?

Answer 16

Increased risk of adverse effects

Must be injected slowly

Not suitable for oily solutions or poorly soluble solutions

Question 17

What are repository preparations of drugs? Where and how are they typically administered? What are some examples?

Answer 17

Repository or “depot” preparations of drugs give slow, sustained release and are usually given subq or intramuscularly. Antipsychotics are commonly administered this way.

Question 18

How can drugs cross membranes to go from gut to blood (for example)?

Answer 18

Drugs can move

(1) passively via paracellular (between cell), diffusion (VERY common) and facilitated diffusion forms of transport
(2) via primary active transport (ABC (ATP-binding cassette) and ATPase transporters)
(3) via secondary active transport (symports and antiports)

Question 19

What is the MDR gene and why is it relevant? How is it dangerous in cancer?

Answer 19

The MDR gene codes for an ABC (ATP-binding cassette) protein that actively pumps molecules into/out of (usually out of) cells against their conc. gradient. The “MDR” stands for Multi-Drug Resistance, and was originally a way for bacteria to get toxins TF OUTTA HERE BISH.

MDR genes are dangerous in cancer pts because they can pump cancer drugs out of cells…wtaf

Question 20

What kinds of drugs can diffuse across a phospholipid bilayer?

Answer 20

Nonpolar (lipophilic), but they must be SOMEWHAT water-soluble.

It is possible for compounds to be both polar and nonpolar because many contain both acidic and basic sidegroups that can affect the polarity/net charge of the compound.

The overall charge depends on the pK_a of the drug in question, as well as the pH of the solution the drug is in

Question 21

What is another, easier way to express the Henderson-Hasselbalch equation?

Answer 21

10^(pH - pK_a) = Unprot./Prot.

Question 22

Why do drugs with a moderate (~6.4) pK_a easily cross the lipid barrier into the blood stream and stay there (i.e. don’t cross back over)?

Answer 22

In the gut, a very low pH (~1.4) ensures most of the drug is in it’s protonated, uncharged form (HA). This allows the drug to cross the lipid barrier into the plasma. Once in the plasma, the much higher pH (~7.4) allows the drug to dissociate from it’s proton (A- + H+), sequestering it in the plasma compartment.

Question 23

What is an example of a drug that requires an enteric coating, and why is that?

Answer 23

Acetylsalicylic acid, or aspirin, has a pK_a of 3.5, so it is mostly protonated/nonpolar in the stomach (97%), which has a pH of 2.

This allows it to cross the gastric epithelium, where it moves into cells with a pH of 7. This much higher pH allows protons to dissociate from 99% of all aspirin molecules, “trapping” it in the epithelium. It can accumulate here and cause ulcers, so we have to use an enteric coating!

Question 24

How are small drug molecules moved into the renal glomerulus in the kidney? What is this called and what % of drugs are eliminated these ways?

Answer 24

Small drug molecules moving in through afferent arterioles pass freely out of the blood vessel into the glomerulus, and are carried into the urine. ~20% of drug elimination happens via diffusion in this way.

Drugs are also transported by carriers from blood into the proximal tubule (~80%), however non-polar drugs are reabsorbed from the distal tubule back into the blood, avoiding elimination.

Question 25

How can we either help or slow down elimination of a drug? What is an example of a drug overdose this is used on?

Answer 25

We can use ion trapping, where

NaHCO3, sodium bicarbonate (baking soda) is used to alkalinize a drug

and

AlCl3, ascorbic acid, is used to acidify a drug

This is used on phenobarbital, an antiseizure drug with a pK_a of 7.4. This allows it to be resorbed easily (protonated and uncharged in urine, with a pH of 5.4) and prolongs its use. Administration of baking soda alkalinizes urine and allows more phenobarbital to be excreted.

Question 26

Where are active transporters found?

Answer 26

“GRaB the Peanut Butter”

The GI tract

Renal tubule

BB barrier

Placenta

Biliary tract

Question 27

What is a key glycoprotein involved in drug regulation? How many genes for these proteins are there?

Answer 27

About 2000 P-glycoprotein (MDR) genes are present in the body, and can pump drugs across membranes via active transport. They regulate distribution of drugs via…

P-gp pumps drugs across GI tract to regulate absorption

P-gp pumps drugs out of the brain to maintain the BBB

P-gp pumps drug out of some cancer cells to protect them from drug effects

Question 28

How can drug distribution occur? What aqueous volumes do drugs have access to?

Answer 28

Some drugs stay inside the plasma compartment and don’t escape the bloodstream (plasma/component of ECF)

Some leak into interstitial fluid (Interstitial/component of ECF)

Some cross cell membranes and is technically in TBW (intracellular)

Question 29

What is membrane limited distribution? Conversely, what can happen to drugs that cross membranes freely?

Answer 29

Membrane-limited distribution occurs when distribution of a drug is confined to a certain aqueous environment (i.e. poorly accessible in fat)

When drugs can move freely across membranes, they may end up in lipidic compartments–however, this distribution may be flow-limited. (i.e. very accessible in fat) TIME IS IMPORTANT HERE!

Question 30

How does a drug generally distribute into organs?

Answer 30

It depends on the amount of blood flow into the organs.

In vessel-rich organs like the heart, brain, kidney, liver, and endocrine system, this happens quickly with a peak as plasma levels fall

In medium-vessel tissues like muscle and skin, there is a slight delay but a higher peak

In vessel-poor tissues like fat, cartilage, bone, teeth, hair, and ligaments, there is a slow, low and steady rise in drug concentration

Question 31

Why is there a very quick change in plasma concentration of a drug, initially? Why does the slope of plasma concentration decrease (flatten out) in the second phase? What are these phases called?

Answer 31

There are many compartments that the drug can rapidly distribute into in the initial, alpha phase, so the plasma concentration drops very quickly.

In the beta phase, drug begins to be metabolized and eliminated, and leaves the body slowly but completely

Question 32

What can happen to free drug in the plasma compartment? What is an example of a drug that “changes form” in plasma, and what effect does this have on the pharmacokinetics of this drug?

Answer 32

Plasma proteins (P) are present in blood at about 70 mg/mL. Drugs can bind non-specifically to these proteins.

Free drug can distribute, interact with receptors, be metabolized and excreted.

Bound drug is stuck in the plasma compartment. Warfarin, which prevents blood clotting, can keep drug in the system for a longer period of time, slowly releasing it and continuing it’s effect.

Question 33

What is the difference between a large and a narrow therapeutic index?

Answer 33

When 100x the therapeutic concentration of a drug is toxic, it’s therapeutic index (TI) is high

When 2x the therapeutic concentration of a drug is toxic, it’s TI is very narrow

Question 34

What happens when you give phenytoin and warfarin together?

Answer 34

Since both of these drugs are highly protein-bound in plasma, phenytoin (antiseizure) will displace warfarin (anticoagulant) from it’s plasma protein, and significantly raise it’s free concentration. This could cause uncontrolled internal bleeding.

This could also occur in reverse, with excess phenytoin being displaced. This could cause decreased nerve activity, or ataxia.

Question 35

What are clinical conditions that impact protein binding?

Answer 35

Renal failure (decreased albumin levels)

Hepatic failure (decreased albumin synthesis)

Inflammatory state (increased AAG levels, increased drug binding)

Question 36

How does the metabolism of drugs generally occur, and what happens to a drug once it has been metabolized?

Answer 36

Drugs are modified by enzymes that inactivate them (sometimes) and make them easier to excrete

Drugs and their metabolites are excreted via the kidneys, gut, lungs, sweat and milk

Question 37

How can you generally measure the pharmacological effect of/response to a drug?

Answer 37

By measuring plasma concentration of that drug

Question 38

What is the point of therapeutic drug monitoring?

Answer 38

You can sample blood and measure [drug]

This makes sure that blood levels fall within a safe and effective level for most patients, aka conveys a reasonable therapeutic response. This is common for drugs with narrow therapeutic indices.