Pharmacology: Pharmacokinetics

Front 1

What is the single compartment model?

Back 1

*Think of the body as a single tank of body water.
*The different steps (absorption, excretion, metabolism) all have their own rate constants.

Front 2

Discuss the diffusion of drugs in the body:

What determines passive diffusion behavior?

Back 2

*Drugs can travel by Passive Diffusion. Passive diffusion behavior is determined by:
1. Concentration Gradient
2. Lipid Solubility
3. Degree of Ionization is determined by the acid/base qualities of the drug. Only the non-ionized drug can diffuse across membranes (it's lipophilic).

*For bases, the protonated species is the charged species. For acids, the protonated species is the non-charged species (can travel across membranes).

Front 3

How are drugs filtered in the body?

How are drugs moved by active transport in the body?

How are drugs endocytosed in the body?

Back 3

*Filtration:
1) Through aqueous channels.
2) Within membranes and between cells.

*Active transport: Facilitated by energy-dependent transporters:
1) Multidrug resistance p-glycoprotein transporter.
2) Multidrug resistance-associate protein and organic anion transporter.
*These two can transport multiple kinds of drugs.

*Endocytosis: Passage into cell within membrane invagination.

Front 4

When you inject a bolus of IV drug, what does the concentration vs. time plot look like?

What about concentration vs. natural log of time?

Back 4

*Ln time is linear. This tells you that the drug obeys first order elimination kinetics (so, a constant fraction of the drug is being eliminated in a unit of time).
*This shows the rate that the drug leaves the body by ALL of its routes of elimination.

Front 5

What's the ∆ b/t first order and zero order elimination kinetics?

Back 5

*1st order: a constant fraction of the drug is being eliminated in a unit of time. Allows for half life measurements.

*Zero order: a constant amount of the drug is being eliminated in a unit of time (alcohol behaves this way, because its transporters are easily saturated).

Front 6

Distribution of Drugs:
What determines which tissues get the drug fastest? 2

What determines differences in tissue/blood ratios at equilibrium?

Back 6

A. Tissue differences in rates of uptake of drugs:
1) Blood flow.
2) Capillary permeability (limits distribution to brain).
*Think lung, liver, kidney.

B. Differences in tissue/blood ratios at equilibrium are determined by the physical chemical properties of the drug:
1) Dissolution of lipid-soluble drugs in adipose tissue.
2) Binding of drugs to intracellular sites (leads to large Vd).
3) Plasma protein binding; there is free drug and bound drug (which travels to sites of action): P + D <--> PD.

Front 7

What is the apparent volume of distribution? Why do we need it?

How do you calculate it?

Back 7

*A way we can relate the amount of drug in the body to the concentration we can measure in the plasma.
*Needed to calculate a loading dose.
*C0 is an imaginary value. It's extrapolated.

Front 8

Apparent Volume of Distribution:

What are the fluid compartments of a 70kg male in Liters and %BW? Which term do we relate Vd to?

How is Vd predicted?

What is plasma half life proportional to and inversely proportional to?

Back 8

*Fluid compartments of 70 kg subject in liters and % BW:
*Plasma 3-4L (4%).
*Extracellular 14-15L (17%).
*TBW 40-42L (58%).

*Prediction of Vd from physical chemical traits of the drug (some can get into TBW, CNS drugs for example, and some can't!).

*Plasma half-life is directly proportional to Vd and INVERSELY proportional to total clearance of the drug.

Front 9

How much can the Vd of different drugs vary? How does this relate to which fluid compartment the drug is in? Give some examples.

Back 9

Front 10

Define and discuss plots of half life:

What's the equation?

Back 10

*The elimination half-life is the time required for the plasma concentration, as well as the amount of drug in the body to fall to one-half.
*0.693 comes from the ln of the half.
*Takes 4 half lives to remove 94% of the drug for drugs with 1st order elimination kinetics. We also use 4 half lives as the amount before we can attain steady state dosing concentrations.

Front 11

What is bioavailability?

What is bioavailability influenced by?

Back 11

*Bioavailability (F) is the fraction of the dose absorbed into the systemic circulation. This is key to know if you're administering the drug any other way than IV!

*Bioavailability of drugs is influenced by:
1) GI absorption.
2) Metabolism in GI tract and/or liver (First pass effect; means only a fraction of the drug gets into the systemic circulation).

*Pic shows oral administration:

Front 12

How do we calculate a drug's F? What's the equation?

Back 12

*Note that this plot is NOT linearized.
*Answer is expressed as a %. Often ~0.3 or so.

Front 13

What is Biotransformation?

What does it result in?

Back 13

*Biotransformation is the elimination of a drug by chemical modification of the molecule (spontaneous or enzyme catalyzed).

*The product after transformation may have greater, lesser, or quantitatively different pharmacological activity from the parent compound.

Front 14

Biotransformation: What's the ∆ b/t type I and type II reactions?

Back 14

*I: Occur throughout the body; not just in liver.
1) Oxidation (cytoP450 enzymes).
2) Reduction.
3) Hydrolysis.
*Results in an oxidized product; often a reactive intermediate.

*II: Modifications of products of phase I rxns.
1) Acetylation.
2) Methylation.
3) Glucuronidation.
4) Glycine conjugation.
5) Glutathione conjugation.
*Usually (with some exceptions) results in a more water-soluble, inactive product. These are more readily picked up by active transporters and pumped into urine or bile.

Front 15

What are the sources of variation in biotransformation?

Back 15

1. Exposure to drugs, dietary constituents, chemicals.
2. Genetics.
3. Age (neonatal jaundice due to lack of enzymes; aging slows down enzymatic rxns).
4. Disease (liver disease, CHF, others).

Front 16

What is Total Clearance? What's the equation for it?

Back 16

*Total Clearance is the volume of plasma cleared of drug in a unit time. Total Clearance is the sum of the clearances by all routes of elimination.
*Measured in mL/min.
*Note two equations I need to know.

*Note how half life is directly proportional to Vd and INVERSELY proportional to total clearance. When clearance decreases, half life increases.

Front 17

Give some drug examples of how half life changes with age; use digoxin and diazepam.

Back 17

Front 18

How do we calculate renal clearance?

What 3 things determine renal clearance rate?

Back 18

*We measure renal clearance by collecting urine.

*Renal Clearance is determined by:
1) Glomerular filtration.
2) Proximal tubular secretion.
3) Distal tubule reabsorption.

Front 19

Discuss glomerular filtration:
What does NOT get filtered?

Back 19

*Driving force is the hydrostatic pressure within the glomerular capillaries.
*The kidneys receive a large blood supply (25% of CO) via the renal artery with little decrease in hydrostatic pressure.
*20% of the renal blood flow filtered (120mL/min).
*Most small molecules (mw<500) are filtered.
*Protein-bound drugs not filtered.
*GFR of drugs is directly related to the plasma concentration of FREE or nonprotein-bound drug
(as plasma concentration of drug increases the glomerular filtration of drug increases).

Front 20

Discuss Proximal Tubule Secretion:
What does secretion rate depend on?

Back 20

*An active process that is saturable and selective.
*Drug is transported against a concentration gradient.
*Carrier system is capacity limited.
*Active tubular secretion rate depends on renal plasma flow.

*The Organic anion transporter is for acid drugs
*The Organic cation transporter is for basic drugs
*There can be competition between 2 acid drugs for the organic anion transporter.
*There can be competition between 2 basic drugs for the organic cation transporter.
*Protein binding does NOT affect secretion.

Front 21

Discuss Distal Tubule Reabsorption:

What determines % ionization?
What determines increased or decreased excretion here?

Back 21

*Passive reabsorption of lipid-soluble, unionized drug.

*% Ionization depends on Henderson-Hasselbalch.

*An Acid drug in alkaline urine has increased excretion. A Basic drug in acidic urine has increased excretion. We can manipulate these characteristics to manipulate excretion.

Front 22

What does the HH equation have to say about where the drug will preferentially go in the distal tubule? Why is this significant?

Back 22

*% Ionization: H-H (pH Partition Hypothesis).

*Compartment in which the drug is more ionized will contain a greater concentration of drug (trapping).
*Figure shows a basic drug trapped in an acid environment.

*Important because this influences EXCRETION!

Front 23

Summary table of the properties of renal drug elimination properties:

Back 23

Front 24

What are our famous indicators for Renal Clearance?

Back 24

Front 25

What does the value of a drug's renal clearance rate tell us about how the drug is handled by the kidney?

Back 25

Front 26

Drug Z, an organic acid with pKa of 3.0, has a renal clearance of 180 ml/min in a 70-kg male subject. One can conclude that the renal clearance of drug Z:

a) Approximates the renal plasma flow.
b) Indicates that drug Z is partially reabsorbed from the renal tubules.
c) Is likely to increase upon acidification of the urine.
d) May increase when another organic acid is administrated at the same time.
e) Indicates renal elimination partly by tubular secretion of drug Z.

Back 26

e) Indicates renal elimination partly by tubular secretion of drug Z.

Front 27

In multiple dose regimens, how do we achieve therapeutic steady states?

What's the equation for steady state concentration?
What's the equation for loading dose? Why would we need a loading dose?

Back 27

*IV infusion is the way to go.

*For infusion:
-INPUT is the infusion rate constant (Ko).
-OUTPUT is the amount in the body (Vd x Css) times the elimination rate constant (k).
-For drugs with 1st order elimination, it takes 4 half-lives to reach 94% of steady state. Therefore, some drugs have long half lives and require a LOADING DOSE.

Front 28

If you want to get to steady state faster, can you just increase the drug infusion rate?

Back 28

*No way, bro. You just end up with a higher final steady state concentration. If you want to get to SS faster, use a LOADING dose.

Front 29

So, SS maintenance is pretty easy to understand with IV infusion. But that sucks. How do we calculate how to achieve steady state with orally taken drugs?

Back 29

*For repetitive dosing:
-INPUT is the fraction of the dose absorbed (bioavailability, F) times the dosing rate (D/tau, for example 5mg of amoxicillin q8h).
-OUTPUT is the amount in the body (Vd x Css) times the elimination rate constant (k).
*Think of the Css as input/output.

Front 30

*In normal 70-kg subjects drug A has a half-life of 4 hours and a recommended infusion rate of 10 mg/min.

*In a 70-kg patient with renal failure, the volume of distribution of drug A is like that found in normal subjects, but its total clearance is only half as large.

*An appropriate infusion rate of drug A for this patient would be:

2.5 mg/ml
5 mg/ml
10 mg/ml
20 mg/ml
40 mg/ml

Back 30

5 mg/ml; because you don't want too much drug to accumulate!

Front 31

What does oral administration look like on a plasma concentration vs. time plot?

Back 31

Front 32

Since the plasma concentration fluctuates over time with oral drug administration, how do you keep things within the therapeutic window?

Back 32

*Gotta time the dosing to hit when you're at Cmin.

Front 33

What's the amount of drug in the body if a drug is given every half life of the drug?

Back 33

Front 34

10 mg of Drug X is injected intravenously q8h.

The elimination half-life of drug X is 8 hr.

What is the total amount of Drug X in the body after 3 days?

Back 34

THIS IS A TRICK. Could be on step1.

ANSWER: 20mg. Just twice the dose.