Pharmacokinetics

Question 1

What determines the rate of a drug entering the site of action?

Answer 1

1) Absorption- movement of drug from the site of administration to the blood
2) Distribution- delivery of drug from the blood to the tissues and target site(s)

Question 2

Why are ionized drugs not well absorbed?

Answer 2

The degree of ionization will affect the partition coefficient and therefore the extent of diffusion.

Question 3

What does a larger pKa indicate for an acid?

Answer 3

The larger the pKa the weaker the acid (opposite is true for bases).

Remember that compounds ionize at the opposite pH. Acids ionize at basic pH (vice versa). In an overdose, sample for acidic drugs in the blood (basic) and basic drugs in the stomach (acidic).

Question 4

Name 7 mechanisms of drug transport across a membrane.

Answer 4

1) Passive diffusion
2) Filtration
3) Bulk flow
4) Active transport
5) Facilitated transport
6) Ion-pair transport (forms a complex with an ion to cross the membrane)
7) Endocytosis

Question 5

What is the partition coefficient?

Answer 5

Partition coefficient is the ratio of concentrations of a compound in the two phases of a mixture of two immiscible liquids at equilibrium.

It is essentially a measure of how hydrophilic/hydrophobic a drug is.

Question 6

Describe the properties of oral drug absorption.

Answer 6

• High blood supply
• High absorption of drugs that have a high partition coefficient (lipophilic/hydrophobic)
• Drug absorption is 4x faster in the mouth than in GI and transit time is fast.

Question 7

Describe the properties of sublingual drug absorption.

Answer 7

• High absorption => dissolved in saliva and then passed into a highly vascularized sublingual area
• Bypasses the GI and goes directly to the blood stream

Question 8

Describe the properties of drug absorption in the stomach.

Answer 8

• Primary function is NOT absorption*
• Only weak acids are absorbed (most drugs are weak bases)
• Can get “ion trapping” of weak bases that are absorbed back from the blood, into the stomach in the non-ionized form and are then ionized and poorly reabsorbed

Question 9

Describe the properties of drug absorption in the small intestine.

Answer 9

• Large surface area, single layer of cells, rich and high volume blood supply
• Most drugs are absorbed in the proximal jejunum
• Most drugs are transported by passive diffusion, so pKa of drug and pH of lumen are critical
• If the transit time is decreased then absorption is limited

Question 10

Describe the properties of drug absorption in the large intestine.

Answer 10

• Less absorption than the small intestine (decreased surface area, less vascularized, increased solid luminal contents)
• Rectal suppositories are useful for patients with emesis, GI surgery/obstruction, uncooperative (children) or unconscious, or to avoid hepatic metabolism

Question 11

List factors that affect GI absorption.

Answer 11

• Gastric emptying time
• Intestinal motility
• Food composition
• Formulations of drugs
• Metabolism and digestion

Question 12

Describe the properties of drug absorption in the lung.

Answer 12

• Inhaled gases, anesthetics, aerosols, smokes, dusts, etc
• Large surface area, thin cell layer, highly vascularized, large blood flow
• High partition coefficient => lipophilic/hydrophobic
• Anesthetics cross very easily, difficult to remove
• Toxicants can easily enter the body through the lung

Question 13

Describe the properties of drug absorption via the skin.

Answer 13

• Local absorption instead of systemic dosing due to slow diffusion
• Slow diffusion can be utilized for long term dosing (skin patches-nicotine)
• Many toxins can enter through the skin or can be carried by solvents, soaps, etc though skin
• Highest absorption via eyes/scrotum; lowest via hands/feet

Question 14

Describe the properties of intramuscular/subcutaneous drug absorption

Answer 14

• Advantages => rapid, precise, large volumes, does not have the complications of IV
• Disadvantages => painful, causes tenderness, local tissue necrosis, possible microbial contamination, and nerve damage

Question 15

Describe the properties of intravenous drug absorption/

Answer 15

• Advantages of IV => direct to blood, so circumvents entire absorption process. useful for drugs with narrow therapeutic index, poor absorption, or problems with metabolism. This is an extremely rapid method of transport
• Disadvantages of IV => in the case of overdose, cannot remove drug or block/slow absorption. There is a risk of embolism, microbial contamination, local necrosis, or immune reaction if too concentrated or rapid delivery.

Question 16

What are the factors that influence drug distribution (6)?

Answer 16

1) Capillary permeability
2) Blood flow to tissue mass ratio (perfusion rate)
3) Regional differences in pH
4) Transport mechanisms available
5) Extent of plasma protein binding => most drugs are bound reversibly to plasma protein but only unbound drugs can pass through capillaries and membranes, be metabolized, and have pharmacological effect
6) Permeability characteristics of specific tissue membrane

Question 17

What is the most important protein for drug binding?

Answer 17

Albumin is the most important protein for drug binding. It is present in high concentrations and has a net negative charge. Albumin can bind hydrophobic drugs at lipophilic sites (high partition coefficient). Albumin’s binding sites are non-specific so many drugs can bind and compete for binding.

Question 18

Describe the selective accumulation of drugs in the kidney.

Answer 18

Kidney has a CO of 20-25% and is therefore susceptible to drug toxicity.

Question 19

Describe the selective accumulation of drugs in the eye.

Answer 19

Melanin (retinal pigment) can bind drugs

Question 20

Describe the selective accumulation of drugs in fat.

Answer 20

Fat can accumulate drugs with high partition coefficients but due to low blood flow drugs are slow to enter/exit fat. However, during fasting fat can release drug boluses/toxin stores => essentially a sink for drugs

Question 21

Describe the selective accumulation of drugs in the lung.

Answer 21

The lung has 100% CO and can selectively accumulate basic amines.

Question 22

Describe the selective accumulation of drugs in bone/teeth.

Answer 22

Drugs are absorbed into the crystal matrix. Permits slow entry and release of drugs.

Question 23

Which drugs can pass the blood brain barrier?

Answer 23

Only high partition coefficient (lipophilic), non-ionized free drug can pass through cells at the blood brain barrier. Inflammation can increase permeability and leave the brain susceptible to toxicants.

Question 24

What are the limitations presented by the blood testis barrier?

Answer 24

Like the blood brain barrier, the blood testis barrier has tight capillary junctions that can impede therapy => cancer chemotherapy for testicular and germ cell cancers.

Question 25

Which drugs pass through the placental barrier?

Answer 25

The placental barrier is not really a barrier. High partition coefficient drugs can readily pass through the placenta and it should be assumed that the dose of the drug given to the mother is what is given to the fetus.

Question 26

Define pharmacodynamics.

Answer 26

Pharmacodynamics is what the drug does to the body.

Question 27

Define pharmacokinetics.

Answer 27

Pharmacokinetics is what the body does to the drug.

Question 28

What is the one compartment model?

Answer 28

The simple one compartment model assumes that:

• The body is a single homogenous fluid filled compartment.
• An IV administration results in an instantaneous release of drug into the compartment
• The drug is instantaneously distributed homogeneously in the compartment
• The drug is eliminated primarily by metabolism (liver) and/or physical removal (kidney)

Question 29

What is the multi-compartment model?

Answer 29

The multi-compartment model demonstrates that:

• Many drugs are modeled poor by one compartment and require two+ compartment sot model their pharmacokinetic behavior.
• Examples: 1) drugs that are distributed rapidly to highly perfused tissues and more slowly to other tissues and 2) drugs that are metabolized rapidly or very slowly

Question 30

What type of kinetics does drug elimination follow?

Answer 30

Elimination usually follows first order kinetics=> a constant fraction of drugs is removed by elimination per unit time

If the route of elimination is saturated, it can follow zero order kinetics => where a constant amount of drug is removed/unit time.

Question 31

What is T1/2?

Answer 31

T1/2 is the time it takes to decrease a given concentration in the blood by half either through elimination from the body or movement to another compartment.

T1/2 =ln2/K=0.693/K ; where K is the elimination constant

T1/2 is dependent on clearance and the volume of distribution.

Question 32

What is the primary factor that defines elimination rate?

Answer 32

Clearance is the primary parameter that defines the elimination rate.

Clearance = Elimination constant x Volume of distribution
(Cl =K x Vd)

To assess clearance in patients, relative renal excretion of most drugs correlates well with creatinine clearance (24hrs)

Question 33

What is the Area Under the Curve (AUC) and how do we interpret it?

Answer 33

The AUC is the space underneath the curve in a drug’s blood concentration vs time graph. A drug’s AUC and graphically shape represent a ratio of the amount of drug in circulation and the clearance of the drug

For accurate dosing a drug’s fractional dose should be determined:
F = AUC (oral)/AUC (IV)

Question 34

In chronic administration how long does it generally take to reach steady state at a constant infusion rate?

Answer 34

It takes approximately about 4 half lives to reach steady state at a constant infusion rate.

Steady state concentration is dependent on the infusion rate, Ko, and clearance.

Note that time to steady state is independent of dose and depends on only the rate of elimination K(el)

Loading dose = steady state concentration x distribution volume