PK and PD

Question 1

Pharmakinetics (PK):

“What the body does to the drug”

ADME

absorption
distribution
metabolism
excretion

Goal: Control the amount of drug exposure

Answer 1

PK is what the body does to a drug during the processes of drug ADME.

Question 2

(PD) Pharmacodynamics:

“What the drug does to the body”, so there is this-

Relationship between drug concentration at the site of activity (receptor) and effects (therapeutic and toxic).

Goal: To control drug response

Answer 2

PD is, what the DRUG does to the human body.

Question 3

When a drug is given Intravascularly (e.g. intravenously (IV) or intraarterially), _______________ is NOT required because the drug enters directly into the blood stream.

Answer 3

absorption

Question 4

If a drug is administered Extravascularly, drug absorption occurs as the drug moves from the site of administration to the bloodstream.

Answer 4

oral, sublingual, buccal, IM, SC, transdermal, inhaled, topical, ocular, intraocular, intrathecal and rectal products.

Question 5

Most oral drug absorption occurs in the ______

Answer 5

small intestine, because of the large surface area and permeable membrane.

Question 6

ABSORPTION:

Oral drug is taken and gets dissolved in stomach.

Then drug goes into the Small intestine [where MOST Drug absorption occurs]

After drug is absorbed, drug ENTERS PORTAL VEIN and travels to the Liver.

At the Liver, the drug is METABOLIZED before it reaches systemic circulation; this is also called 1st PASS METABOLISM.
“or”
the drug can be excreted back into the small intestine transported through bile where it can be reabsorbed. This is also called enterohepatic recycling.

Answer 6

gut = GI system, stomach, intestines and colon

Question 7

Systemic Absorption can occur via:

1)

2)

Answer 7

1) Active transport
- utilizes transporter proteins
- drugs are moved across the gut wall via transport proteins that are normally used to absorb nutrients from food
- Requires Energy

2) Passive transport
- concentration gradient [area of HIGH concentration (e.g. gut lumen) to an area of LOW concentration (e.g. blood)]
- No energy needed

Question 8

Local vs Systemic Effects:

Intravascular administration [NO ABSORPTION PHASE]
- Intravenous
- Intra-arterial

Extravascular administration [ABSORPTION OCCURS]
- oral (SYSTEMIC activity)
- sublingual (SYSTEMIC activity)
- buccal (SYSTEMIC activity)
- IM (SYSTEMIC activity)
- SC (SYSTEMIC activity)
- dermal (LOCAL activity)
-
- pulmonary (LOCAL activity)
- Topical ocular (LOCAL activity)
- intraocular (LOCAL activity)

Question 9

ABSORPTION is dependent on a process called ___________

Answer 9

DISSOLUTION

Question 10

Dosage form Dissolution and Drug solubility:

Dissolution: _______

Dissolution rate (is described by the Noyes-Whitney equation) can be increased by:
___________ & __________

Solubility is increased with _________

Answer 10

Dissolution
- process of drug dissolving in the GI tract and release active drug

Dissolution rate (Noyes-Whitney equation) can be increased by:
- reducing particle size (micronized formulations)
- increasing surface area

Ways to limit drug degradation for drugs destroyed by the gut
- Enteric coating [e.g. Dulcolax, Entocort-budesonide]

Solubility is increased with hydrophilic drugs (water-loving)

“Poorly soluble drugs are generally lipophilic, or fat-loving”

Freely soluble drugs are generally hydrophilic, or water loving.

Question 11

In General:

Answer 11

• IV, SL, ODT, IR tablet, ER tablet.

Question 12

• percentage of drug (0-100%) absorbed from the extravascular (usually oral) administration relative to intravascular administration (IV)
• High > 70% = drug with good absorption
• (e.g.
• Low < 10% = drug with poor absorption
  -(e.g. bisphosphonates, like ibandronate have low bioavailability)

Some drugs have 100% oral bioavailability:
- Levofloxacin, Linezolid
- Allows for therapeutic interchange between IV and oral formulations

Some drugs

Answer 12

Bioavailability (F):
- the extent of drug absorption into the systemic circulation.
- reflects the percentage of drug absorbed from the extravascular compared to the intravascular administration.

Question 13

Bioavailability (F):

Is affected by:

Answer 13

• Solubility
• Dissolution (when a drug dosage form dissolves and releases active ingredient)
• Route of administration
• other factors (drug particle size, drug charge, Fat-loving, Water-loving)

Question 14

Calculating Bioavailability:

• can be calculated using the (AUC) area under the plasma concentration time curve, or AUC.
• the (AUC) area under the curve represents the TOTAL systemic exposure to the drug following administration.
• Equation:

Answer 14

F(%) = 100 x (AUC extravascular / AUC intravascular) x (Dose intravenous / Dose extravascular)

Question 15

Different Dosage Forms of the same drug (e.g. tablet vs solution) may have different bioavailability’s.

What formula can be used to calculate an equivalent dose of a drug when the dosage form is changed?

Answer 15

Dose of NEW DOSAGE FORM =

(Amount of drug absorbed from current dosage form) / (Bioavailability (F) of NEW DOSAGE FORM)

Question 16

-
-

Antibodies can be used to target distribution of therapeutics to specific tissues and organs.

Answer 16

• process by which drug molecules move from systemic circulation to tissues and organs.

_____________________________________________________________________________
- lipophilicity (affinity for lipids)
- molecular weight
- ionization status (charged or uncharged)
- protein binding

Question 17

Factors that favor passage across membranes and greater drug distribution to the tissues include:

-
-

Answer 17

• HIGH Lipophilicity
  [drug will favor going into tissues rather than staying in the blood]
• Low molecular weight
  [big bulky compounds don’t cross membranes very well, so a LOW MOLECULAR WEIGHT will favor drug being able to distribute into tissue rather than staying in the blood]
• Low protein binding
  [Many drugs are bound to proteins, if a drug has LOW PROTEIN BINDING that means there is more of the free drug in the blood, meaning there is more drug available to distribute to the tissues.] {versus a drug that is very highly protein bound, it is going to stay on the protein, which is in the bloodstream.)
• unionized status
  [UNCHARGED MOLECULES are those that are able to cross membranes more easily and distribute to tissues, whereas a charged molecule is more likely to stay in the blood]

Question 18

Albumin-

Answer 18

the primary protein responsible for drug binding

Question 19

Only the unbound (free) form of a drug can interact with receptors, EXERT THREAPEUTIC OR TOXIC EFFECTS and be cleared from the body.

Answer 19

If a drug is highly protein bound (>90%) AND serum albumin is low (<3.5g/dL), THEN a higher percentage of the drug will be in the unbound form and the patient may experience therapeutic or even adverse effects at what appears to be anormal or subtherapeutic level.

Question 21

Volume of Distribution (Vd): Equation

Answer 21

= Amount of DRUG in BODY
_________________________________
Concentration of DRUG in Plasma

Question 21

Volume of Distribution (Vd):

Answer 21

• reflects how large of an area in the patient’s body the drug has distributed into and is based on the properties of the drug.
• the volume of distribution relates the amount of drug in the body to the concentration of the rug measured in plasma (or serum).

Question 22

Volume of Distribution (Vd):

• Is NOT a physical volume
• It is a THEORETICAL value, sometimes called the “apparent” volume of distribution.
• NOT AN EXACT PHYSICAL VALUE THAT IS MEASURED, but is a helpful parameter used to make inferences regarding how widely a drug distributes throughout the body.

• ## a Small Vd means =
• a Large Vd means =

Answer 22

• a Small Vd means = confined to plasma or extracellular space
• “drug is not going anywhere”

• a Large Vd means = wide distribution to all body tissues

Question 23

Metabolism:

Original chemical form is called the ____________

Other chemical forms are called _______

Occurs primarily in gut and liver.

Answer 23

• process by which a drug is converted from its original chemical structure into other chemical forms. This is to facilitate elimination from the body.
• “Parent drug”
• metabolites

Question 24

The primary sites for drug metabolism are ________ and ________.

Answer 24

gut and liver.

Question 25

First -Pass metabolism:

ex. First pass metabolism of lidocaine is so extensive that the drug CANNOT be given orally- it must be given IV.

Many nonoral, extravascular methods of administration (e.g. transdermal, buccal, sublingual) bypass first pass metabolism entirely. Rectal administration partially avoids first pass metabolism.

Answer 25

is the metabolism of a drug before it reaches the systemic circulation, which can dramatically reduce the bioavailability of an oral formulation.

Question 26

Phase 1 reactions:

Answer 26

• Hydrolysis
• Oxidation
• Reduction

“Phase 1 reactions provide a reactive functional group on the compound that permits the drug to be attacked by Phase II reaction enzymes.”

For example-

Question 27

Phase II reactions:

Answer 27

• Conjugation
• ## Glucuronidation

Question 28

Excretion:

The primary route of excretion for most drugs is the ______

Answer 28

• the process of irreversible removal of drugs from the body.

Excretion can occur through the KIDNEYS (urine), LIVER (bile—>feces), GUT (feces), LUNGS (exhaled air) and SKIN (sweat).

• KIDNEYS (rectal excretion)
  “rectal excretion can be increased by adjusting the acidity of the urine”. For a weak base, increase excretion by acidifying the urine. For a weak acid, increase excretion by alkalizing the urine.”

Question 29

Clearance & Area Under the Curve:

Answer 29

• ## the volume of blood from which drug is removed per unit of time.
• ## Proportionality constant between the rate of drug elimination and the drug concentration.
• Clearance stays constant with changing drug concentrations (except in non-linear kinetics)

Question 30

Clearance equation:

Answer 30

= Rate of Elimination / Drug concentration
___________________________________________________________
Following IV administration, remember bioavailability (F) = 1
= Dose/AUC

Question 31

Clearance: describes the rate of drug removal in a certain volume of plasma over a certain amount of time.

Since the liver and kidneys clear most of the drug, most drug elimination occurs at a steady state (called the rate of elimination).

This is true of drugs following first-order kinetics.

Clearance is the efficiency of drug removal form the body and is described by the following equation:

Answer 31

Cl = Rate of Elimination / Drug Concentration

• The Rate of Elimination (Re) has units of mass per time (e.g. mg/hr) and Drug Concentration has units of amount per volume (e.g. mg/L)

“because the rate of elimination is difficult to assess clinically, another method is used to calculate clearance of a drug from the body:

F x Dose = Cl x AUC

Question 32

Remember if giving a drug (IV) the bioavailability (F) is equal to _____________

Answer 32

1

Question 33

ZERO vs FIRST ORDER pharmacokinetics:

Most drugs follow __________ elimination.

Answer 33

1st order elimination or “first order kinetics”

WHICH IS, where a CONSTANT PERCENTAGE OF DRUG IS REMOVED PER UNIT OF TIME.

ex. for example a 325mg dose of Tylenol is eliminated at the same rate as a 650mg dose.

For example:

Hour 0- (20%) removed in previous hour
Hour 1- (20%) removed in previous hour
Hour 2- (20%) removed in previous hour
Hour 3- (20%) removed in previous hour

When, drug level is at STEADY-STATE, doubling the dose approximately doubles the serum concentration.

So with 1st order kinetics if we gave a dose of 50mg of drug AND it increases the seru level by 1mg/L, we would expect that if we give another 50mg of drug that it will increase level another 1mg/L.

Question 34

ZERO vs FIRST ORDER pharmacokinetics:

Zero-order elimination:

Answer 34

A CONSTANT amount of drug (mg) is removed per unit time no matter how much drug is in the body.

ex.
Hour 0 - 0
Hour 1 - 300mg amount of drug removed in previous hour
Hour 2 - 300mg amount of drug removed in previous hour
Hour 3 - 300mg amount of drug removed in previous hour

Question 35

MICHAELIS-MENTEN kinetics:

• also called _____1______
• There is a maximal rate of metabolism (Vmax).
• ## Michaelis-Menten constant (Km) is the concentration at 1/2Vmax
• Initially, when increasing the concentration of a drug, {when lots of enzyme is free and available for the drug} these drugs interestingly at low concentrations will follow _____2______.
• **However, there is a point where metabolism becomes ____3_____.
• So there is a maximum rate of metabolism defined as ____4___
  ____________________________________________________________________________- Increasing the dose leads to disproportionate increases in concentration
  ____________________________________________________________________________
  —–Doubling the dose of these drugs can more than double the serum concentration.
• This can lead to toxicity
• Drugs that exhibit Michaelis-Menten kinetics include: ___5_____
  ——– Using a proportion to calculate a new dose is NOT APPROPRIATE.
  ——– Dosing adjustments must be made cautiously to avoid toxicity and in small increments.

Answer 35

2- 1st order kinetics
3- saturated

4- Vmax
5- phenytoin, theophylline, voriconazole

Question 35

The concentration at which the rate of metabolism is half maximal is defined as the ________________________

Answer 35

Michaelis-Menten constant (Km)

Question 37

• this is calculated from the equation:

Answer 37

• the elimination rate constant is the fraction of the drug that is eliminated (cleared) per unit time.

ke= Cl / Vd

Question 38

Half-life AND Steady state:

• Half-life (t1/2)- can be used to estimate % of drug remaining or % of steady-state achieved.
• greater than > 95% of drug is eliminated after 5 half-lives
• **95% of steady-state will be achieved after 5 half-lives [assuming NO LOADING DOSE].

Answer 38

Half-life, is the time that it takes for a drug concentration (and drug amount) to decrease by 50%

Half life can be used to determine:
- the drug washout, or the time that it will take for most of the drug to be eliminated from the body.
OR “can also be used”
- to determine how long it will take for the patient to achieve steady state

remember Steady-state: the point where drug intake = drug elimination

Question 39

Half-life (t1/2):

can be calculated using formula-

Answer 39

t1/2 = 0.693/ ke

Question 40

Loading Dose:
- may be necessary for some drugs to rapidly achieve therapeutic concentrations.
- helpful when half-life is long relative to the frequency of administration (dosing interval).
-
- Loading Dose can be calculated using:

Answer 40

Loading Dose = (Desired Concentration x Vd) / F