Module 1 Section 2 (Pharmacokinetics)

Question 1

What is pharmacokinetics?

Answer 1

The term used to describe the processes involved in the journey of a drug through the body.

Question 2

What are the 4 key processes of pharmacokinetics?

Hint: ADME

Answer 2

1) Absorption: The movement of a drug from the site of administration into the blood.
2) Distribution: The movement of a drug from the blood to the site of action and other tissues.
3) Metabolism: Also known as biotransformation; the conversion of a drug into a different compound, usually into a more water-soluble compound.
4) Excretion: The removal of a drug and its products from the body.

Acting together, these four factors determine the concentration of drug in the blood, which in turn determines the concentration of drug at the site of action.

Question 3

True or false: the physical-chemical properties of a drug, such as solubility in water and fat, will determine how readily a drug gets to the site of action.

Answer 3

True

Question 4

After a drug is ingested, does all of the drug end up in the blood?

Answer 4

During the process of absorption, not all of the drug ends up in the blood, or in other words, the bioavailability (i.e. the fraction of an administered dose that reaches the blood in an active form) differs between drugs.

Question 5

What is the bioavailability of an injected drug?

Answer 5

A drug dose given intravenously is placed directly into the blood and is therefore considered to be 100% bioavailable.

Question 6

What is the bioavailability of a drug administered orally?

Answer 6

The bioavailability of drugs administered orally can vary anywhere from 5% to 100% of the administered dose.

Question 7

What are a few key components of the absorption process?

Answer 7

1) The breakdown of excipients (i.e. fillers and binders that are inactive and serve as a vehicle or medium for the drug to enter the body)
2) The dissolution in gastrointestinal fluids
3) The crossing of biological membranes

Question 8

Describe the 3 steps of absorption.

Answer 8

1) Release of the drug from the dosage form. - A capsule or tablet is not pure drug, but contains a number of excipients. Therefore, after a tablet is ingested, it must break into small particles to release the drug.
2) The drug must then dissolve in the fluids of the GI tract before it can be absorbed into the blood.
3) For a drug to be absorbed into the blood and to be distributed to the sites of action, storage, and excretion, it must be able to cross biological membrane.

Question 9

What are the ways in which drugs cross biological membranes?

Answer 9

1) Diffusion through aqueous pores
- Drugs w/ small molecular weights that’re water soluble can move across membranes by first dissolving surrounding cells and then by passing through the small openings b/w cells.
- From high to low concentration.

2) Diffusion through lipids
- Most drugs aren’t small enough to pass through aqueous pores so it uses this way to cross membranes.
- Drugs with higher molecular weights pass through the membrane by dissolving in the lipid portion of the membrane.
- These drugs also flow down a concentration gradient
- The ability of a drug to cross the membrane and be absorbed depends on its lipid solubility
- The most important process used by drugs to cross membranes

3) Active or carrier-mediated transport
- Drugs bind to proteins (transporters) which carry molecules across a membrane
- Once bound, the drug courier complex moves across the membrane and releases the drug on the other side of the membrane
- Can move down a concentration gradient. However, it can also be an active process requiring energy and can move a drug against a concentration gradient (low to high concentration)

Question 10

True or false: Lipid soluble drugs pass through the membrane by dissolving in the lipid portion of the membrane and flowing down a concentration gradient to the other side of the cell membrane.

Answer 10

True

Question 11

Explain why lipid solubility is important in a drug’s ability to cross membranes.

Answer 11

The unionized (uncharged) form is lipid soluble and readily crosses membranes, whereas the ionized (charged) form is water soluble and does not readily cross the lipid membrane.

The degree of ionization depends on the pH of the environment (e.g. stomach, intestine, or blood) and the pKa of the drug, where the pKa of a drug is the pH where a drug is 50% ionized and 50% unionized.

Question 12

True or false: a large percentage of drugs are weak acids or weak bases.

Answer 12

True

Question 13

What is a weak acid with regards to drugs? Give an example

Answer 13

A weak acid is a drug that is a neutral molecule that can dissociate into a negatively charged molecule and a proton.

Ex: Aspirin goes from the unionize, lipid soluble form to the ionized, water soluble form.

Question 14

What is a weak base with regards to drugs? Give an example

Answer 14

A weak base is a drug that is a neutral molecule that can combine with protons to form a positively charged molecule.

Ex: norepinephrine goes from the ionized, water soluble form to the unionized, lipid soluble form.

Question 15

How does an acidic environment impact the absorption of a drug?

Answer 15

In an acidic environment, an excess of protons are available, so the unionized form of a weak acid, and the ionized form of a weak base will predominate.

Therefore, a weak acid will be primarily in the lipid soluble form in an acidic environment (such as your stomach).
- The protonated form of a weak acid is the neutral, lipid soluble form of the drug.

Question 16

How does a basic environment impact the absorption of a drug?

Answer 16

In a basic environment, few protons are available, so the ionized form of a weak acid, and the unionized form of a weak base will predominate.

Therefore, a weak base will be primarily in the lipid soluble form in a basic environment (such as your intestine).
- It will be deprotonated, thus making it a neutral molecule.

Question 17

Under acidic conditions, which drug is lipid soluble?

Answer 17

Weak acid

Question 18

Under basic conditions, which drug is lipid soluble?

Answer 18

Weak base

Question 19

What occurs when aspirin enters the stomach?

Answer 19

When aspirin (pKa 3.5) is in the stomach, which has a pH of 1 to 2, it will predominantly be in the protonated form, which is the unionized, lipid soluble form of the drug.

Question 20

What occurs when aspirin enters the intestine?

Answer 20

If aspirin is in the intestine, which has a pH greater than 5, then the aspirin will predominantly be in the ionized, water soluble form of the drug and won’t readily cross membrane.

Question 21

What occurs when norepinephrine enters the stomach?

Answer 21

In the acidic stomach, the protonated form of norepinephrine (pKa 8.6) will predominate, which is the ionized, water soluble form of the drug.

Question 22

What occurs when norepinephrine enters the intestines?

Answer 22

As norepinephrine moves into the intestines, the fraction of protonated norepinephrine will decrease, as the pH of the intestines is closer to the pKa of norepinephrine.

Therefore, more norepinephrine will be in the unionized, lipid soluble from of the drug, allowing more drug to be absorbed from the intestine than in the stomach.

Question 23

True or false: ionized (charged) = water soluble; unionized (uncharged) = lipid soluble

Answer 23

True

Question 24

True or false: the greatest amount of absorption is going to occur when drugs are in the unionized or uncharged form

Answer 24

True

Question 25

True or false: a weak acid is a neutral molecule that can dissociate into a negatively charged molecule and a proton

Answer 25

True

Question 26

True or false: a weak base is a drug that’s a neutral molecule that can combine with protons to form a positivelty charged molecule.

Answer 26

True

Question 27

Under acidic conditions, what form of weak acids and bases predominate?

Answer 27

More protons are available…

Unionized (uncharged) form of a weak acid.

Charged form of a weak base.

Weak acid is absorbed more.

Question 28

Under basic conditions, what form of weak acids and bases predominate?

Answer 28

Few protons are available (less things paired up so a proton is unpaired)

Ionized (charged) form of a weak acid

Unionized (uncharged) form of a weak base.

Weak base is absorbed more.

Question 29

True or false: the lower the pH of the environment relative to the pKa of the drug, the greater the fraction of drug that will be in the protonated form.

Answer 29

True

More of the drug will be in the protonated form

• Unionized (charged) weak acid
• Ionized (uncharged) weak base

Question 30

True or false: the higher the pH of the environment relative to the pKa of the drug, the less the fraction of drug that will be in the protonated form.

Answer 30

True

More of the drug will be in the unprotonated form

• Ionized (charged) weak acid
• Unionized (uncharged) weak base

Question 31

True or false:

Answer 31

True

Drugs that’re weak acids will be absorbed best from acidic conditions such as the stomach.

Drugs that’re weak bases will be absorbed best from basic conditions such as the intestine.

Question 32

Clinical Application Question: Proton pump inhibitors are used to reduce heartburn by inhibiting stomach acid secretion. Aspirin has a pKa of 3.5, meaning that it will be in the unionized, lipid soluble form of the drug in environments that have a pH less than 3.5. A person taking a proton pump inhibitor will change the pH of their stomach from 1-2 to around 5. What do you think would happen if someone was taking both a proton pump inhibitor and asprin?

Answer 32

The overall absorption of aspirin will be decreased in someone who is taking a proton pump inhibitor. The pH of someone’s stomach who is taking a proton pump inhibitor (pH ~5) is greater than aspirin’s pKa, so the ionized, water soluble form of aspirin will predominate and the drug will no longer be absorbed in the stomach. The pH of the intestines is greater than 5, so aspirin will not be absorbed in the intestines either.

Question 33

Why are most drugs absirbed in the intestines?

Answer 33

Both acids and bases can be absorbed from the intestine, as the large surface area of the intestine can compensate for the drug’s degree of ionization.

Question 34

Describe drug absorption in the stomach.

Answer 34

The drug first reaches the stomach where it usually disintegrates and dissolves. Some proportion of drugs are absorbed from the stomach, depending on the pKa.

Question 35

Describe drug absorption in the small intestine.

Answer 35

Because of its permeability, large surface area, and high blood flow, the small intestine is the primary site for drug absorption. Absorption may be limited by the short transit period of the drug through the small intestine (2-4 hours).

Question 36

Describe drug absorption in the large intestine.

Answer 36

The colon is usually a poor site for drug absorption due to its low permeability and relatively small surface area. Nevertheless, some drugs are absorbed at this site because of the long period of transit (24-48 hours).

Question 37

What is distribution?

Answer 37

For a drug to act, it must move from its site of absorption to other areas of the body, including the site of action.

Question 38

True or false: the concentration of the drug in the blood is a good indicator of the expected pharmacological effect.

Answer 38

True

This is because the concentration of drugs at the site of action is in equilibrium with the concentration of drug in the blood.

Question 39

True or false: the rate at which drugs distribute in and out of a particular organ depends on the blood flow to that organ.

Answer 39

True

For instance, the greater the blood flow to an organ, the more rapidly drugs reach that organ. The opposite is also true.

Question 40

Describe the effects of distribution in the drug thiopental.

Answer 40

After IV injection of thiopental (an ultra short-acting anesthetic), the concentration of the drug in the blood is high. The concentration in the brain, which has high blood perfusion, will be elevated and the patient will fall asleep. At this time, the concentration of thiopental in muscle and fat, which have low blood perfusion, is low.

After a few mins, the concentration of the drug in muscle/fat increases and the concentration in blood decreases, causing the drug to leave the brain and move into the blood. As the concentration of the drug in the brain decreases, the patient will awake, usually after about 15-30 minutes.

Thus, the action of the thiopental has been terminated by the drug redistributing from the brain into muscle and fat, even through the drug has not been removed from the body.

Question 41

What forms do drugs exist in the sites of distribution?

Answer 41

Free drug and drug bound to protein.

Question 42

What occurs when a drug is bound to protein in the blood? Provide an example.

Answer 42

It is not able to cross membranes and is therefore unable to produce its pharmacological effect or be readily excreted by the kidney.

Ex: many drugs are bound to albumin (a plasma protein made by the liver that serves as a transport protein for large anions) and other proteins in the blood, and this bound drug cannot get to the site of action and therefore cannot produce a pharmacological effect.

Question 43

What is the purpose of the blood brain barrier?

Answer 43

The blood brain barrier limits the access of many drugs to the brain and spinal cord.

Question 44

Is the placenta permeable to drugs?

Answer 44

The placenta is very permeable to drugs and most drugs reach the fetal tissue.

Question 45

Where do fat soluble drugs often accumulate?

Answer 45

Fat soluble drugs will accumulate in fat cells, and since blood flow to fatty tissue is limited, drugs will leave fat tissue slowly.

Question 46

What is metabolism (biotransformation)?

Answer 46

Metabolism, or biotransformation, is the conversion of a drug to a different chemical compound.

Question 47

Why will a drug undergo biotransformation? Provide an example.

Answer 47

A drug will undergo biotransformation if it needs to be converted into another compound so it can exert it’s effect or be eliminated from the body.

Biotransformation can result in detoxification of a compound, meaning it converts a toxic compound to a nontoxic compound, or it can result in bioactivation of a compound, meaning it converts an inactive compound to an active compound.

Ex: codeine is converted in the body to morphine, which is the compound that causes the relief of pain. In other words, codeine is bioactivated to morphine through the process of biotransformation.

Question 48

Where do most biotransformations occur?

Answer 48

The liver

Question 49

True or false: in most cases, biotransformation reactions involve the conversion of drugs into more water-soluble compounds.

Answer 49

True

Once water-soluble, the drug can be eliminated form the body by the kidneys.

Without biotransformation, some chemicals that are very lipid soluble would never be excreted from the body.

Question 50

Where else may biotransformation occur?

Answer 50

It can also occur in the kidneys, intestines, lungs, skin, and most other organs.

Question 51

What biotransformation reactions divided into?

Answer 51

Phase 1 and Phase 2 reactions

Question 52

What is the purpose of phase 1 reactions?

Answer 52

The purpose of a phase 1 reaction is to add or unmask a functional group so that the phase 2 reactions can add a large water-soluble component, usually glucuronic acid or sulfate, to allow excretion by the kidney.

Question 53

What are some of the common phase 1 reactions?

Answer 53

• Oxidative reactions via cytochrome P450
• Other oxidative reactions
• Hydrolysis of esters and amides.

Question 54

What are cytochrome P450s and what do they do?

Answer 54

The cytochromes P450 (CYPs) are a family of enzymes located primarily on the smooth endoplasmic reticulum in the liver.

These enzymes perform the majority of biotransformation.

Question 55

How many enzymes of the CYP family do humans have? Which one is highly used in biotransformation?

Answer 55

Humans have approximately 18 enzymes of the CYP family involved in drug biotransformation.

The enzyme CYP 3A4 biotransforms about 50% of all drugs used clinically, which can lead to drug interactions, as drugs given at the same time can compete for the attention of CYP 3A4.

Question 56

What is the function of CYPs?

Answer 56

The function of CYPs are to bind the substrate and activate oxygen.

Question 57

How do CYPs demonstrate genetic variability? Provide an example.

Answer 57

This means that genes coding for the enzymes can exist in several forms.

In some people, the gene that codes for the enzyme produces an ineffective enzyme (and these people are slow metabolizers), while in other people the gene that codes for the enzyme can exist in multiple copies (polymorphism = these people are fast metabolizers).

Ex: CYP 2D6 has at least three genetic variants, resulting in slow, normal, and fast metabolizers. One drug affected by CYP 2D6 genetic variants is the activation of codeine to morphine.

Question 58

What are other oxidative reactions? Provide 2 examples.

Answer 58

Other oxidative reactions not mediated by CYPs are the oxidation of amines and the dehydrogenation of alcohol. These reactions are mediated by alternative enzymes.

Ex: amines, such as epinephrine and norepinephrine, are oxidized by the enzyme monoamine oxidase.

Ex: the dehydrogenation of alcohol to an aldehyde and acid occurs through the action of the enzymes alcohol dehydrogenase and aldehyde dehydrogenase

Question 59

What is the hydrolysis of esters and amides? Provide an example.

Answer 59

These drugs are converted to the acid and the corresponding alcohol or amine by carboxyl esterases found in the liver, blood, GI tract, and other tissues.

Ex: the muscle relaxant succinylcholine is metabolized by these enzymes.

Question 60

What are phase 2 reactions?

Answer 60

Phase 2 reactions add a large water-soluble moiety to the phase 1 biotransformation product, making the metabolite water-soluble for excretion by the kidney.

Question 61

What are the 4 main phase 2 conjugation enzymes?

Answer 61

1) UDP-glucuronosyltransferase (UGT): forms a glucuronide
2) Sulfotransferase (SULT): forms a sulfate
3) Glutathione transferase (GST): forms a glutathione conjugate
4) N-Acetyl transferase (NAT): forms N-acetylated metabolite

Question 62

Fill in the blanks

Phase 1 Metabolism:

• Reactions occur via ___ __ enzymes
• Heme containing enzymes = ___ loving
• ___ and accept electrons

Drug + ___ + NADPH -> Drug*-O + ___ + NADP+

They produce a more ___ molecule to be easily removed from the body.

Answer 62

Phase 1 Metabolism:

• Reactions occur via cytochrome P450 enzymes
• Heme containing enzymes = oxygen loving
• Donate and accept electrons

Drug + O2 + NADPH -> Drug*-O + H2O + NADP+

They produce a more hydrophilic molecule to be easily removed from the body.

Question 63

Fill in the blanks:

Phase 2 metabolism:
- Conjugation: attachment of small ___molecules onto the drug.

Drug + Acetyl - CoA -> Drug - ___+ CoA

It makes the drug less ___ soluble and more easily excreted.

Answer 63

Phase 2 metabolism:
- Conjugation: attachment of small polar molecules onto the drug.

Drug + Acetyl - CoA -> Drug - Acetyl + CoA

It makes the drug less lipid soluble and more easily excreted.

Question 64

True or false: drugs are metabolized from lipopholic to hydrophilic

Answer 64

True

Question 65

Provide an example of a drug undergoing phase 1 and phase 2 biotransformation.

Answer 65

Drug —(Phase 1 P450; adds a functional group)—> Drug-OH —(Phase 2; adds water soluble moeity ex: sulfate group)—> Drug-SO3H ——> water soluble drug excreted by kidney

Question 66

P450 enzymes are used in which type of biotransformation reactions?

a) Phase 1 reactions
b) Phase 2 reactions
c) Both phase 1 and phase 2 reactions
d) Neither phase 1 or phase 2 reactions

Answer 66

a) Phase 1 reactions

Question 67

What is the first pass effect? Provide an example.

Answer 67

The first pass effect refers to the biotransformation and inactivation of a drug during absorption from the intestine.

Ex: a drug is administered orally. Blood leaving the small intestine will enter the liver via the portal vein, giving the liver, with all its enzymes, an opportunity to metabolize the drug before it enters the general circulation. This is called the first pass effect and it can reduce the amount of active drug reaching the blood and hence the site of action.

Therefore, only a small fraction of the drug makes it through the first pass.

Question 68

How can we bypass the first pass effect?

Answer 68

1) Give more of the drug (most common).

2) Bypass the liver so that it reaches the tissues before the liver
- Ex: IV drug = most common route (problem = inconvinent for pts)
- Ex: topical -> nitroglycerine
- Ex: Transdermal route -> given less than orally for the same results
- Ex: vagina ring formulation
- Ex: nicrotine (via smoking, nasal spray or nicotine gun)

Question 69

What factors affect biotransformation? (4)

Answer 69

1) Genetic factors: genetic variants in enzymes can result in fast metabolizers or slow metabolizers
2) Age: the amount of biotransformation enzymes are decreased at birth and in the elderly (>60)
3) Disease states: any disease that affects the liver will affect biotransformation enzymes (e.g. alcoholic hepatitis, biliary disease, liver cancer, etc.)
4) Drug interactions can occur when two drugs are competing for the same enzyme, or when one drug inhibits the biotransformation of another drug.

Question 70

Clinical Application Question:

Two individuals undergo surgery to repair abdominal hernias. The first individual is a 70 year old male with liver disease. The second individual is a 40 year old healthy male. Post-surgically, both patients are given the same dose of codeine, however, the 70 year old patient continues to complain about pain, while the 40 year old patient does not. What is one potential explanation that you could give for this difference between the two patients?

Answer 70

Age and disease state.

Remember that in the body codeine is bioactivated into the pain-relieving entity morphine by CYP 2D6. Both increased age and liver disease will decrease biotransformation enzymes. It is likely that the 70 year old male with liver disease was unable to convert enough codeine into morphine to experience relief of pain. Therefore, he may need either an increased dose of codeine, or be given morphine instead of codeine.

Question 71

What is excretion? What is the main route?

Answer 71

Drug excretion is moving the drug and its metabolites out of the body.

The main route of elimination for drugs is through the kidneys. However, drugs can also be eliminated through the GI tract, glandular activity (e.g. milk, sweat, and saliva), and the lungs.

Question 72

What are the 3 processes of renal excretion through the kidneys?

Answer 72

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

Question 73

Describe the process of glomerular filtration? What is the glomerular filtration rate?

Answer 73

Most drugs pass from the glomerulus into the Bowman’s capsule and then into the proximal tubule of the kidney.

The glomerular filtration rate, which is the amount of blood that passes through the glomeruli each minute, can be used to determine how well the kidneys are working. In kidney disease, the glomerular filtration rate is decreased, and hence excretion of drugs is also decreased. This can result in prolonged effects of drugs, as they are in the body longer. Since drugs are predominantly eliminated by renal clearance, any disease that affects blood flow (and hence glomerular filtration rate) will also affect excretion of drugs.

Question 74

What is the glomerular filtration rate? How is it affected in kidney disease?

Answer 74

The glomerular filtration rate, which is the amount of blood that passes through the glomeruli each minute, can be used to determine how well the kidneys are working.

In kidney disease, the glomerular filtration rate is decreased, and hence excretion of drugs is also decreased.

• This can result in prolonged effects of drugs, as they are in the body longer.
• Since drugs are predominantly eliminated by renal clearance, any disease that affects blood flow (and hence glomerular filtration rate) will also affect excretion of drugs.

Question 75

What is passive tubular reabsorption?

Answer 75

Generally, the concentration of drug is higher in the renal tubules than in the blood. Therefore, some lipid soluble drugs can be reabsorbed back into the blood, as they are moving down the concentration gradient.

Question 76

True or false: reabsorption of drugs can be modified by altering the pH of urine.

Answer 76

The ionized form of a drug is the water-soluble form of a drug, which will be excreted in the urine. As such, basic urine will increase the excretion of acidic drugs, while acidic urine will increase excretion of basic drugs.

Question 77

What is active tubular reabsorption? Provide an example.

Answer 77

Some active transporters in the renal tubule move drugs from the blood into the urine to be excreted.

Ex: Penicillin is a drug actively secreted into the renal tubule. Due to this active secretion, about 80% of a dose of penicillin is cleared from the body within three to four hours after administration. The drug probenicid can be given to block the secretion of penicillin.

Question 78

Describe the role of the GI tract in excretion?

Answer 78

A number of drugs that are metabolized and conjugated in the liver are excreted into the GI tract via the bile for elimination with the feces.

Drugs that bind to proteins in the GI tract will not be absorbed.

Question 79

Describe the role of the other bodily fluids in excretion?

Answer 79

Drugs are found in all body fluids, including milk, saliva, and sweat.

Quantitatively, these routes have a minor role in drug excretion from the body. However, drugs in sweat and saliva can be used to detect drugs of abuse.

Question 80

Describe the role of the lungs in excretion? Provide an example.

Answer 80

Volatile drugs can be exhaled via the lungs.

Ex: anesthetics and alcohol.

Question 81

Drug X is a weak base with a pKa of 8. Which one of the statements regarding Drug X is correct?

a) Drug X will be absorbed best in basic conditions
b) The ionized form of Drug X is lipid soluble
c) In the stomach, Drug X will be unionized
d) In the intestine, Drug X will be predominantly in the charged form

Answer 81

a) Drug X will be absorbed best in basic conditions

Question 82

Which one of these statements regarding biotransformation is correct?

a) Phase 1 biotransformation involves conjugation reaction.
b) The enzyme CYP 2A6 biotransforms about 50% of clinically used drugs
c) An example of a phase 2 reaction is an oxidative reaction by CYP 3A4
d) Phase 1 reactions add or unmask a functional group

Answer 82

d) Phase 1 reactions add or unmask a functional group