Drug Properties and Drug Absorption

Pharmacokinetics (PK)

what the body does to the drug; the movement of drugs within the body

Pharmacodynamics (PD)

what a drug does to the body; the effects of drugs and mechanisms of action

ADME

acronym that describes how drugs will move within the body

What does ADME stand for?

Absorption

Distribution

Metabolism

Excretion

If a drug is administered IV, what step of ADME will be skipped?

Absorption; will go straight into distribution instead

What happens to a drug that is not absorbed by the body?

it will go straight into elimination by the body (will not be distributed or metabolized)

Some drugs that are excreted in the GI tract will be...

resorbed due to enterohepatic recirculation

Two types of dosages:

1.) single dosage

2.) repeated dosage

single dosage

given as:

weight of drug/weight of animal (mg/kg OR mg/lbs)

single dosage drugs can also be given as...

BSA (body surface area) (mg/M^2)

Repeated dosages are always given as ________

rates

Two examples of when a repeated dosage is given:

1.) infusions

2.) multiple single dosages within a day

repeated dosage: infusions

given as a rate:

weight of drug/weight of animal/min (mg/kg/min)

repeated dosage: multiple single dosages

mg/kg/# hours (ex: twice daily or every 12 hrs)

In order for a drug to be absorbed, it has to go through several cell __________

membranes

Three mechanisms of drug transport through membranes:

1.) simple diffusion

2.) carrier-mediated (facilitated diffusion and primary active transport)

3.) pinocytosis

simple diffusion

Diffusion that doesn't involve a direct input of energy or assistance by carrier proteins

facilitated diffusion

process of diffusion in which molecules pass across the membrane through cell membrane channels

primary active transport

Active transport through a membrane channel that relies directly on the hydrolysis of ATP

pinocytosis

process by which a cell engulfs a molecule and internalizes it as a vesicle

Most drug absorption occurs through what mechanism?

passive diffusion across cell membranes!

passive diffusion

movement of substances across a semipermeable membrane with the concentration gradient

What type of molecules diffuse easily across cell membranes?

uncharged, lipophilic (hydrophobic) molecules

What type of molecules do NOT diffuse easily across cell membranes?

charged, hydrophilic molecules

Most drugs are either _______ acids or ________ bases

weak; weak

Weak acid drugs are __________ when protonated and ________ when unprotonated

uncharged/unionized

charged/ionized

Weak base drugs are __________ when protonated and ________ when unprotonated

charged/ionized

uncharged/unionized

Therefore, in the stomach (acidic pH) are most weak acid drugs well absorbed?

yes! they are uncharged and will therefore diffuse across the cell membrane

Therefore, in the stomach (acidic pH) are most weak base drugs well absorbed?

no! they will be charged and therefore not cross the cell membrane

pKa

the pH at which the concentrations of its charged/ionzied and uncharged/unionized forms are equal

If pH is less than pKa, weak ________ will be mostly uncharged/unionized

acids

If pH is greater than pKa, weak ________ will be mostly uncharged/unionized

base

Neutral drugs

drugs that remain uncharged regardless of the pH

Do neutral drugs readily cross cell membranes?

yes!

Quaternary amines

drugs that are charged independently of the pH

Will quaternary amines readily cross cell membranes?

no! the passage across membranes is greatly impaired and the drug must be injected in the blood to be effective

Drug absorption

the process of movement of an unchanged drug from the site of administration to systemic circulation

Examples of factors when considering what the route of administration for a drug should be

-concentration of drug needed

-where in the body is the drug needed

-how fast is the action needed

-safety of treatment

-cost of treatment

Two routes of administration:

1.) enteral

2.) parental

enteral route of administration

oral, sublingual, rectal; administration via the GI tract

Pathway of oral drugs through the body

absorbed by stomach/intestines --> portal vein --> liver --> metabolization in the liver --> hepatic vein --> systemic circulation

Drugs given orally will be absorbed via the...

first pass effect/metabolism

First pass effect/metabolism

drug metabolism that occurs in the liver during oral absorption of drugs into the systemic circulation

Pathway of sublingual drugs through the body

venous return directly to systemic circulation

Pathway of rectal drugs through the body

venous return directly to systemic circulation

Therefore, sublingual and rectal drugs will ________ undergo the first pass effect/metabolism

not!

How is absorption of drugs affected in the intestines?

since the intestines have such a large surface area due to villi & microvilli, pH will have a small impact on drug absorption of weak acids and weak bases

Four factors that can alter enteral administration:

1.) pH of body fluid

2.) motility

3.) adsorption/complexation

4.) blood flow

How does pH of body fluid alter enteral administration?

ex:

-pH of the stomach is very acidic and therefore will absorb weak acids

-antacids will raise the pH of the stomach

How does motility alter enteral administration?

ex: diseases such as diarrhea will increase motility and therefore decrease the absorption of the drug

How does adsorption/complexation alter enteral administration?

some foods cannot be given with food because they might complex with compounds present in the food that will decrease their absorption

How does blood flow alter enteral administration?

If blood flow is good, there will be better, faster absorption, but if blood flow is poor (such as critically ill animals), there will be slower, reduced, and less reliable absorption

Parenteral drug administration

drug administered by means other than through the GI tract, such as IV, IM, SC, or transdermal

Four main factors affecting the drug absorption of any drug:

1.) physical form (liquid vs tablet)

2.) solubility of the drug

3.) pKa of the drug

4.) routes of administration

Plasma level time curve

A graph of the concentration of a drug measured in a series of blood samples over time

Three phases of a plasma level time curve:

1.) absorption phase

2.) peak absorption phase

3.) post-absorption phase

absorption phase

Time that drug is moving from the site of administration to blood

During the absorption phase, absorption rate is ________ _____ elimination rate

greater than

peak absorption phase

Time during which the drug is being absorbed the highest amount across a membrane into the blood

During the peak absorption phase, absorption rate is ________ ___ elimination rate

equal to

post-absorption phase

Time that a drug is being eliminated after is has been metabolized

During the post-absorption phase, absorption rate is ________ ___ elimination rate

less than

1

absorption phase

2

peak absorption phase

3

post absorption phase

4

elimination phase

AUC

The area under the plasma level-time curve, representing the total drug exposure over time

Minimum effective concentration

amount of drug required to produce a therapeutic effect; if below this line, the drug will not have desired effect

Minimum toxic concentration

amount of drug that will produce a toxic effect; if above this line, the drug will be toxic

Therapeutic range

that concentration of drug in the blood serum that produces the desired effect without causing toxicity; between the minimum effective concentration and minimum toxic concentration

1

AUC

2

minimum effective concentration

3

minimum toxic concentration

4

therapeutic range

bioavailability

A measure of the extent of drug absorption for a given drug and route

Three examples of solid form enteral drugs:

1.) tablets

2.) capsules

3.) powders

First step of tablet and capsule breakdown

disintegration

disintegration

breaking up into particles

Second step of tablet and capsule breakdown

dissolution

dissolution

process of the drug going into solution

First step of powder breakdown

dissolution

What is the limiting step of bioavailability of all solid form drugs?

the dissolution step!

Two examples of liquid form enteral drugs:

1.) suspensions

2.) solutions

Liquid form enteral drugs will be readily...

absorbed

*don't need to undergo disintegration or dissolution

Three reasons why some drugs cannot be given orally:

1.) too irritating to GI mucosa

2.) inactivated by pH in the stomach or bacteria in intestines

3.) rapidly metabolized by the liver

List enteral drug forms from those with highest availability to lowest bioavailability:

solutions

suspensions

powders

capsules

tablets

coated tablets

sustained release

Five main forms of parenteral drugs:

1.) intravenous (IV)

2.) inhalation

3.) intraperitoneal (IP)

4.) intramuscular (IM)

5.) transdermal

List the parenteral drug forms from fastest absorbed to slowest absorbed

intravenous (IV)

inhalation

intraperitoneal (IP)

intramuscular (IM)

transdermal

There is no absorption phase on a plasma concentration curve for what parenteral drug form?

intravenous; given directly to the blood and absorbed in seconds!

Intramuscular drugs are absorbed faster than ________ drugs

oral

Three intravascular drug adminsitrations

1.) intravenous

2.) intra-arterial

3.) intra-cardiac

Formulations of intravascular drugs

aqueous solutions/miscible with water (pH 4-10)

Two advantages of intravascular drugs

-rapid (no absorption phase)

-predictable and titratable

Three disadvantages of intravascular drugs

1.) requires skill

2.) sterility of solution and needle

3.) no recall

Formulations of intramuscular drugs

aqueous solutions; aqueous suspensions;

oily solutions/suspensions; oil/water emulsions

Two advantages of intramuscular drugs

1.) moderate volumes at multiple sites

2.) depot formulations (slow release)

Three disadvantages of intramuscular drugs

1.) pain and irritation

2.) possible tissue damage

3.) absorption depends on blood flow

Formulations of subcutaneous drugs

aqueous solutions; suspensions; solid implants

Two advantages of subcutaneous drugs

1.) large volumes can be injected

2.) pet owner can easily be trained

Disadvantage of subcutaneous drugs

pain and irritation possible