Pharmacokinetics and pharmacodynamics (Katzungs, Ch 3. Trans 4)

Question 1

Volume of distribution (V) relates the amount of drug in the body
to the concentration of drug (C) in blood or plasma

Answer 1

V = Amt of drug in body/C
**Drugs with very high volumes of distribution have much higher concentrations in extravascular tissue than in the vascular compartment, ie, they are not homogeneously distributed.

Question 2

Clearance of a drug is the factor that predicts the rate of elimination in relation to the drug concentration:

Answer 2

CL = Rate of elimination/C
**It is important to note the additive character of clearance. Elimination of drug from the body may involve processes occurring in the kidney, the lung, the liver, and other organs. Dividing the rate of elimination at each organ by the concentration of drug presented to it yields the respective clearance at that organ.

Question 3

REMEMBER
For most drugs, clearance is constant over the concentration range encountered in clinical settings, ie, elimination is not saturable, and the rate of drug elimination is directly proportional to concentration

Answer 3

Rate of elimination = CL x C

• *This is usually referred to as first-order elimination.
• *When clearance is first-order, it can be estimated by calculating the area under the curve (AUC) of the time-concentration profile after a dose. Clearance is calculated from the dose divided by the AUC

Question 4

REMEMBER
For drugs that exhibit capacity-limited elimination (eg, phenytoin, ethanol), clearance will vary depending on the concentration of drug that is achieved

Answer 4

Capacity-limited elimination is also known as mixed-order, saturable, dose/concentration-dependent, nonlinear, and Michaelis-Menten elimination.

Question 5

REMEMBER

FOR CAPACITY-LIMITED ELIMINATION, Rate of elimination = Vmax x C/Km + C

Answer 5

• *The maximum elimination capacity is V max

* *Km is the drug concentration at which the rate of elimination is 50% of V max

Question 6

REMEMBER
FOR CAPACITY-LIMITED ELIMINATION, At concentrations that are high relative to the Km, the elimination rate is almost independent of concentration. If dosing rate exceeds elimination capacity, steady state cannot be achieved: The concentration will keep on rising as long as dosing continues

Answer 6

This pattern of capacity-limited elimination is important for three drugs in common use: ethanol, phenytoin, and aspirin.
**Clearance has no real meaning for drugs with capacity-limited elimination, and AUC should not
be used to describe the elimination of such drugs.

Question 7

In contrast to capacity-limited drug elimination, some drugs are
cleared very readily by the organ of elimination, what type of elimination does these drugs display?

Answer 7

Flow-dependent elimination

• *The elimination of these drugs will thus depend primarily on the rate of drug delivery to the organ of elimination
• *Blood flow to the organ is the main determinant of drug delivery, but plasma protein binding and blood cell partitioning may also be important for extensively bound drugs that are highly extracted

Question 8

The time required to change the amount of drug in the body by one-half during elimination (or during a constant infusion).

Answer 8

Half-life (t 1/2)

**t 1/2 = 0.7 x V/CL

Question 9

As a “rule of thumb” how many half-lives must elapse after starting a drug-dosing regimen before full effects will be seen

Answer 9

Four half-lives

• *This refers to the graph of time course of drug accumulation and elimination (katzung, figure 3-3)
• *Fifty percent of the steady-state concentration is reached after one half-life, 75% after two half-lives, and over 90% after four half-lives.

Question 10

REMEMBER
Disease states can affect both physiologically related primary pharmacokinetic parameters (volume of distribution and clearance). A change in half-life will not necessarily reflect a change in drug elimination.

Answer 10

For example, patients with chronic renal failure have decreased renal clearance of digoxin but also a decreased volume of distribution; the increase in digoxin half-life is not as great as might be expected based on the change in renal function. The decrease in volume of distribution is due to the decreased renal and skeletal muscle mass and consequent decreased tissue binding of digoxin to Na+ /K+-ATPase.

Question 11

If the dosing interval is shorter than four half-lives, accumulation will be detectable (refer to katzung figure 3-3)

Answer 11

Whenever drug doses are repeated, the drug will accumulate in the body until dosing stops.

Question 12

Accumulation factor = 1/fraction lost in one dosing interval
** = 1/1 - fraction remaining
**Accumulation is inversely proportional to the fraction of the
dose lost in each dosing interval. The fraction lost is 1 minus the fraction remaining just before the next dose. The fraction
remaining can be predicted from the dosing interval and the half-life

Answer 12

FOR EXAMPLE
For a drug given once every half-life, the accumulation factor is 1/0.5, or 2.
**The accumulation factor predicts the ratio of the
steady-state concentration to that seen at the same time following the first dose. Thus, the peak concentrations after intermittent doses at steady state will be equal to the peak concentration after the first dose multiplied by the accumulation factor.

Question 13

Defined as the fraction of unchanged drug reaching the systemic circulation following administration by any route

Answer 13

Bioavailability
**The area under the blood concentration-time curve (AUC) is proportional to the extent of bioavailability for a drug if its elimination is first-order

Question 14

REMEMBER

For an intravenous dose of the drug, bioavailability is assumed to be equal to unity

Answer 14

For a drug administered orally, bioavailability may be less than 100% for two main reasons—incomplete extent of absorption across the
gut wall and first-pass elimination by the liver

Question 15

REMEMBER
Following absorption across the gut wall, the portal blood delivers the drug to the liver prior to entry into the systemic circulation. A drug can be metabolized in the gut wall or even in the portal blood, but most commonly it is the liver that is responsible for metabolism before the drug reaches the systemic circulation. In addition, the liver can excrete the drug into the bile. Any of these sites can contribute to this reduction in bioavailability, and the overall process is known as first-pass elimination.

Answer 15

The effect of first-pass hepatic elimination on bioavailability is expressed as the extraction ratio (ER):
ER = CLliver/Q
**where Q is hepatic blood flow, normally about 90 L/h in a person weighing 70 kg.

Question 16

The systemic bioavailability of the drug (F) can be predicted from the extent of absorption (f) and the extraction ratio (ER):

Answer 16

F = f x (1-ER)

Question 17

The mechanism of drug absorption is said to be zero-order when the rate is independent of the amount of drug remaining in the gut, eg, when it is determined by the rate of gastric emptying or by a controlled release drug formulation

Answer 17

In contrast, when the dose is dissolved in gastrointestinal fluids, the rate of absorption is usually proportional to the gastrointestinal concentration and is said to be first-order.

Question 18

The hepatic first-pass effect can be avoided to a great extent by using these method

Answer 18

Sublingual tablets and transdermal preparations and to a lesser extent by use of rectal suppositories
**Sublingual absorption provides direct access to systemic—not portal—veins. The transdermal
route offers the same advantage.
**Drugs absorbed from suppositories in the lower rectum enter vessels that drain into the inferior vena cava, thus bypassing the liver. However, suppositories tend to move upward in the rectum into a region where veins that lead to the liver predominate. Thus, only about 50% of a rectal dose can be assumed to bypass the liver

Question 19

REMEMBER
In most clinical situations, drugs are administered in such a way as to maintain a steady state of drug in the body, ie, just enough
drug is given in each dose to replace the drug eliminated since the preceding dose.

Answer 19

At steady state, the dosing rate (“rate in”) must equal the rate of elimination (“rate out”): Dosing rate = Rate of elimination

• • = CL x TC (target concentration)
• *Thus, if the desired target concentration is known, the clearance in that patient will determine the dosing rate.

Question 20

If the drug is given by a route that has a bioavailability less than 100% the equation is:

Answer 20

Dosing rate (oral) = dosing rate/F (oral)
**If intermittent doses are given, the maintenance dose is calculated from: Maintenance dose = dosing rate x dosing interval

Question 21

A target plasma theophylline concentration of 10 mg/L is desired to relieve acute bronchial asthma in a patient. If the patient is a nonsmoker and otherwise normal except for asthma, the mean clearance given is 2.8 L/h/70 kg. Since the drug will be given as an intravenous infusion, F = 1. what is the dosing rate?

Dosing rate = CL x TC
= 2.8L/h/70kg x 10 mg/L
= 28 mg/h/70 kg

Answer 21

If the asthma attack is relieved, the clinician might want to maintain this plasma level using oral theophylline, which might be given every 12 hours using an extended-release formulation to approximate a continuous intravenous infusion. If F (oral) is 0.96 and the dosing interval is 12 hours, the size of each maintenance dose would be:
Maintenance dose = Dosing rate/F x dosing interval

** 28 mg/h/ 0.96 x 12 hours = 350 mg

Question 22

REMEMBER
When the time to reach steady state is appreciable, as it is for drugs with long half-lives, it may be desirable to administer a loading dose that promptly raises the concentration of drug in plasma to
the target concentration

Answer 22

Loading dose = amt in the body immediately following the loading dose

• • = V x TC
• *When intermittent doses are given, the loading dose calculated from equation above will only reach the average steady-state concentration and will not match the peak steady-state concentration. To match the peak steady-state concentration, the loading dose can be calculated from equation: Loading dose = maintenance dose x accumulation factor

Question 23

Abnormal clearance may be anticipated when there is major impairment of the function of what organs?

Answer 23

Kidney, liver and heart

Question 24

REMEMBER

Small volume of distribution = increased plasma concentration (drug is binded to plasma proteins)

Answer 24

large volume of distribution = decrease plasma concentration (drug is binded to tissues)

Question 25

No matter how high the drug concentration goes, a point will be reached beyond which no further increment in response is achieved, what pharmacodynamic variable is being referred to?

Answer 25

Maximum effect (Emax)

Question 26

This pharmacodynamic variable is reflected by the concentration required to produce 50% of maximum effect

Answer 26

sensitivity of the target organ to drug concentration (C50)

Question 27

It is the single most important factor determining drug concentrations

Answer 27

Clearance
**The interpretation of measurements of drug concentrations depends on a clear understanding of three factors that may influence clearance: the dose, the organ blood flow, and the intrinsic function of the liver or kidneys

Question 28

What are the factors affecting protein binding? why is it important in determination of clearance?

Answer 28

1. Albumin concentration - some drugs are extensively bound to plasma albumin
2. alpha-acid glycoprotein concentration
3. Capacity-limited binding protein

**Change in protein binding can give an interpretation of altered clearance when in fact drug elimination is not altered

Question 29

What is the significance of fat-free mass (FFM) in volume distribution?

Answer 29

Some drugs do not readily penetrate fat (gentamicin and digoxin). If a patient is obese volume of drug sitribution should be calculated from FFM

Question 30

REMEMBER
Patients with edema, ascites, or pleural effusions offer a larger volume of distribution to the aminoglycoside antibiotics (eg, gentamicin) than is predicted by body weight

Answer 30

In such patients, the weight should be corrected as follows: Subtract an estimate of the weight of the excess fluid accumulation from the measured weight. Use the resultant “normal” body weight to calculate the normal volume of distribution. Finally, this normal volume should be increased by 1 L for each estimated kilogram of excess fluid. This correction is important because of the relatively small volumes of distribution of these water-soluble drugs.

Question 31

3 types of passive transport:

1. simple non-ionic diffusion
2. Filtration
3. Aqueous diffusion

Answer 31

Specialized transport

1. active transport
2. facilitated diffusion
3. pinocytosis
4. exocytosis

Question 32

REMEMBER

• *rapid = hydrophobic, non-ionic molecules
• *slow = ionic large molecules

Answer 32

Simple non-ionic diffusion is not saturable and does not involve carrier protein

Question 33

REMEMBER
Drug must be unionized to penetrate the membrane

**Only the uncharged species (the protonated form for the weak acid; the unprotonated form for a weak base)

Answer 33

Weak acid is a neutral molecule that can reversibly dissociate into an anion and a proton
**Protonated form can penetrate the membrane

Weak base is a neutral molecule that can form a cation by combining with a proton
**Unprotonated form can penetrate the membrane

Question 34

Effect of pH on absorption of weak acids and bases

• *pKa is the dissociation constant. pH (ionized=unionized)
• *The greater is the value of pKa, the weaker will be the acid and the stronger will be the base

Answer 34

If pH > pKa for weak bases, they can be absorbed in the membrane

Question 35

REMEMBER

Urinary acidification accelerates excretion of weak bases and retards that of weak acids

Answer 35

Urinary alkalization accelerates excretion of weak acids and retards that of weak bases

Question 36

For drugs absorbed in the stomach ‐ If the gastric emptying time is decreased, there will be shorter or no absorption as the drug will go directly to the small intestine

Answer 36

For drugs absorbed in the SI - The shorter the gastric emptying time, the faster the drug will be absorbed as it is transported faster to the site of absorption (in this case, the SI).

Question 37

SPEED of absorption

Fastest to slowest (solutioon, capsule, tablet and suspension)

Answer 37

Solution > Suspension > Capsule > Tablet

Question 38

type of bioavailability that More of a concern for pharmaceutical industry/company because your trying to describe the bioavailability of one drug and the bioavailability of the standard/innovator drug

Answer 38

RELATIVE Bioavailability

**Comparison of the AUC of a new drug formulation against the original formulation

Question 39

“You’re trying to compare the bioavailability of the different types of formulations comparing it with the IV drug”

Answer 39

ABSOLUTE Bioavailability

• *Comparison of the AUC of a drug that is given through IV against the one that is given orally
• *When you say of Bioavailability you speak of the AREA UNDER THE CURVE (AUC) – shows clinical effectiveness. It tells you the overall exposure of the patient to the drug.

Question 40

you cannot give them orally because once you give them orally its usually destroyed by stomach ph.

Answer 40

Acid labile

Question 41

5 routes of drug administration

Answer 41

1. Enteral (drugs placed directly in the GI tract
   - sublingual
   - oral
   - rectal
2. parenteral
   - intravenous (100% bioavailability)
   - Intramuscular
   - Subcutaneous
   - Intraperitoneal
   - Intra-arterial
   - Percutaneous
3. Transdermal
4. Inhalation
5. Topical

Question 42

REMEMBER

weak acid binds with albumin

Answer 42

weak base binds with glycoproteins

Question 43

First pass elimination – enzymes in the intestinal flora, mucosa and liver metabolize drugs before they reach general circulation, significantly decreasing bioavailability

Answer 43

o There’s a lesser first pass effect on rectal due to a portion of drug that will not pass the liver
o Upper GIT undergoes first pass effect
o Lower GIT does not undergo first pass effect.

Question 44

Interaction with other substances in GIT

food - depends on the drug; will either reduce or delay

Answer 44

a. Absorption is delayed with food; e.g. amoxicillin, paracetamol, aspirin
b. Absorption is reduced with food; e.g. ampicillin (an aminobenzene drug; that’s why between ampicillin and amoxicillin, it’s better to give amoxicillin because you can still give it with foods without reducing absorption), Isoniazid
c. Absorption is enhanced with food; e.g. beta blockers like metoprolol, propranolol.

Question 45

Major Compartments of the body

Answer 45

o Plasma - 5% of Body weight
o Interstitial Fluid - 6-10%
o Intracellular fluid - 35%
o Transcellular fluid - 2%
o Fat - 20%

Question 46

REMEMBER
Clinical significance of Plasma Protein Binding
1. Delays onset time for drug action
2. Prolongs duration of drug action
3. May require higher dose
4. Protein binding serves as reservoir
5. May cause drug-drug interaction (e.g. Sulfonamides, Warfarin)
6. Diseases may result to hypoalbuminemia
- Reduce drug protein binding
- Increase free drug level (e.g. chronic renal failure)
7. Free form available for metabolism

Answer 46

**Sulfonamide can compete with the Bilirubin binding site. Lead can compete with calcium in bone lattices