Absorption

Question 1

What is pharmacokinetics?

Answer 1

How drugs move through, and are altered by, the body

Question 2

what is pharmacodynamics?

Answer 2

Mechanisms of drug action

Question 3

four main pharmacokinetic processes

Answer 3

• Absorption
• Distribution
• Metabolism
• Excretion

Question 4

what is meant by drug absorption?

Answer 4

The movement of drug from the site of
administration into the systemic circulation

Question 5

what is meant by a drug’s bioavailability? Does the way a drug is administered matter for this measure?

Answer 5

The fraction of an administered dose of drug that reaches the systemic circulation unchanged
-Bioavailability therefore depends on route: IV bioavailability is (by definition) 100%
-Oral bioavailability tends to be the lowest, since the liver, which receives drug from the GI tract, is the major organ for drug metabolism

Question 6

how does the plasma drug concentration of a drug change over time following an oral or IM dose?

Answer 6

-will build up from zero, eventually reaching the MEC (minimum effective concentration) in the blood, where we see the onset of effect.
-will continue to increase, but the rate of increase decreases. Eventually peak effect is reached at max concentration.
-Concentration begins to fall. Eventually falls below MEC, and then concentration continues to taper off slowly

Question 7

what is the duration of action for a drug?

Answer 7

the amount of time for which the concentration of the drug in the plasma is greater than the MEC

Question 8

what is the therapeutic window for a drug?

Answer 8

the plasma drug concentration between the MEC for the desired effect and the MEC for adverse effect

Question 9

What does the rate of absorption of a drug effect?

Answer 9

onset, duration, and intensity of action

Question 10

what type of drug administration is associated with the most rapid absorption?

Answer 10

IV administration - essentially instant

Question 11

very slow absorption of a drug is associated with which administration technique?

Answer 11

Subcutaneous

Question 12

What is a problem that can arise if a drug dose is absorbed too slowly?

Answer 12

MEC may not be reached

Question 13

Routes of drug administration can be classified as either:

Answer 13

1) Enteral
i.e., via the GI tract  portal vein  liver  systemic circulation
Used to refer to the oral route of administration

2) Parenteral
Routes that involve absorption of drug from sites other than the GI tract; drug does not pass through liver before reaching systemic circulation

Question 14

advantages and disadvantages to oral route of drug administration

Answer 14

1) Oral (L. per os; PO)

Advantages:
• Simple; often the most convenient for home administration
• Usually safer than injection

Disadvantages:
• Absorption may be erratic
• Patient/client compliance problems
• Not possible with unconscious patients
• “First-pass” effect
• Too slow for some emergency situations
• Emesis & GI irritation possible; may be ineffective in a vomiting patient

Question 15

what is the first pass effect? How can this be avoided?

Answer 15

Drugs administered orally are absorbed into the portal vein and delivered first to the liver where metabolism may inactivate a percentage of the drug molecules (“first-pass metabolism”) before they have a chnace to reach the target organ

Drugs administered parenterally enter the systemic circulation and reach other tissues before eventually undergoing metabolism in the liver

Question 16

what is sublingual drug administration? What limitation does it have and what are advantages and disadvantages?

Answer 16

2) Sublingual (oral transmucosal)
Absorption through oral mucosa into systemic circulation
(bypasses GI tract)
Limited to fairly lipid-soluble drugs

Advantages:
• No first-pass metabolism

Disadvantages
• Patient must cooperate (not swallow drug)
> relatively easy for human patients;
in vet. med. limited to liquids that are rapidly absorbed from oral cavity
• Significant proportion of dose may be swallowed

Question 17

what are the advantages and disadvantages to administration of a drug via subcutaneous injection?

Answer 17

3) Subcutaneous injection (SC or SQ; “sub-Q”)

Advantages:
• Suitable for solid pellets, insoluble suspensions, oily vehicles (“depot” formulations)
• Safer & easier to administer than IV
• Absorption slower than by IV or IM routes (may also be a disadvantage)

Disadvantages:
• Not suitable for large volumes
• Pain or necrosis possible with irritating drugs, can be severe
• Absorption can be very slow
• Infection possible
• Slow onset of action

Question 18

advantages and disadvantages of IM injection of drug

Answer 18

4) Intramuscular injection (IM)

Advantages:
• Absorption rapid for drugs in aqueous solution
• Oily suspensions form “depot” of drug for slow absorption
• Safer & easier to administer than IV

Disadvantages:
• Local pain possible even with proper administration; hematoma risk; infection possible
• Not suitable for large volumes
• Pain or necrosis possible with irritating drugs, can be severe

Question 19

advantages and disadvantages administering a drug via intravenous bolus injection

Answer 19

5a) Intravenous bolus injection (IV)

Advantages:
• Route of choice in emergencies > rapid onset of activity
• Suitable for large volumes (compared to IM, where no more than ~15 mL should be injected at one site)
• Irritating drugs: become diluted as injection into bloodstream proceeds, but must inject slowly (or use CRI with very irritating drugs)
• Bioavailability is 100%

Disadvantages:
• Higher risk of adverse effects
• Often must inject slowly due to cardiac toxicity risk
• Not for oily or insoluble drugs
• Requires more skill

Question 20

advantages and disadvantages of drug administration via intravenous constant rate infusion

Answer 20

5b) Intravenous constant rate infusion (CRI or “IV drip”)

Advantages:
• Suitable for large volumes (slowly)
• Safest route for irritating drugs, which become diluted (may damage vessel if administered too rapidly)
• Delivery directly into systemic circulation (bioavailability is 100%)

Disadvantages:
• Infection risk from indwelling catheter
• Requires more skill

Question 21

advantages and disadvantages to administering a drug via topical administration

Answer 21

6) Topical administration
Sites such as eye, ear, skin, mucous membranes (conjunctiva, nasopharynx, oropharynx, vagina, colon, urethra)

Advantages:
• Drug delivered to site of need
• Can achieve very high conc’n
> may be effective only at these high concentrations that cannot be safely achieved by systemic administration

Disadvantages:
• May be absorbed systemically
• May not remain in place; can be messy

Question 22

advantages and disadvantages to administering a drug via transdermal administration

Answer 22

7) Transdermal administration
Drug is applied to skin with the intention of having it absorbed into the systemic circulation to produce an effect elsewhere in the body

Advantages:
• Controlled release with prolonged duration of action (e.g., fentanyl patches)

Disadvantages:
• Slow onset of action
• Excessive absorption may occur if blood flow to skin is excessive (e.g., in animals that sweat to lose heat)
> toxic concentrations may be achieved in systemic circulation
• Absorption through damaged skin is enhanced (usually not desirable)

Question 23

what does the term drug ‘formulation’ refer to?

Answer 23

The term “formulation” can be used to refer to:
• The physical form of a medication (e.g., oral tablet; liquid for IV injection), or
• The chemical ingredients in a pharmaceutical
(i.e., both the active drug and any inactive chemicals, preservatives, etc. that comprise a pharmaceutical product ready for administration to the patient by a specified route of administration)

Most of the ‘inactive’ ingredients are present simply to balance pH, to alter flavour, or to produce the desired physical form (aqueous solution, suspension, syrup, gel, solid, etc.)

Question 24

what chemical property do many drugs have, and why is this useful?

Answer 24

Many drugs are weak acids (A) or weak bases (B)

Both un-ionized (no net electrical charge) & ionized molecules are present in solution, which helps the drug move through the body
• Un-ionized: More lipid soluble > can diffuse across membranes
• Ionized: More water soluble > can diffuse through cytoplasm, ECF, etc.
• A single molecule flips between ionized and un-ionized states by binding to or unbinding from hydrogen ions (H+, also known as protons)

Question 25

ionized weak acid has what form, vs unionized weak acid?

Answer 25

Ioinized weak acid: A^- + H^+

Unionized weak acid: AH

Question 26

what type of molecules can diffuse across cell membranes? What does the rate of diffusion depend on?

Answer 26

un-ionized molecules
-for a weak acid: AH
-for a weak base: B

rate of diffusion depends on solubility

Question 27

weak acid has what charge without a proton? With a proton?

Answer 27

negative charge when separated from proton. Neutral charge when united with proton

Question 28

weak base has what charge without a proton? With a proton?

Answer 28

positive charge with proton, neutral charge when separated from proton

Question 29

What determines the proportion of molecules that are ionized?

Answer 29

pKa (ionization constant: acids & bases only)
= pH at which 50% of drug molecules are ionized

> If the pKa of a drug and the pH of the medium are known, the amount of un-ionized drug can be calculated using the Henderson-Hasselbalch equation

Question 30

what drug forms predominate in a proton rich environment? What about a proton poor environment?

Answer 30

-AH and BH+ forms predominate when drug enters environment rich in protons (ie. low pH, pH < pKa)

-A- and B forms predominate when drug enters environment poor in protons (i.e high pH, pH > pKa)

Question 31

Will a weakly acidic drug with a pKa of 4.4 be better absorbed from the stomach (assuming pH = 1.4) or from the intestine (assuming pH = 6.4)?

Answer 31

Stomach - in the more acidic environment (pH < pKa), the weak acid will be protonated, ie. have un-ionized the form AH
> uncharged molecule can diffuse through cell membranes
-at pH > pKa, will have charged form A-; cannot diffuse

Question 32

A weakly basic drug with a pKa of 8.4 is administered orally.
Will it be better absorbed from the stomach (pH 2.4) or the small intestine (pH 6.4)?

Answer 32

intestine - the higher pH means more of the drug will be in state B vs BH+
>molecules of B can diffuse
-note that in both cases here, pH < pKa, but pH is closer to pKa in the intestine so a larger fraction will be in non-protonated form B

Question 33

most oral drugs have what chemical characteristic? Why?

Answer 33

Any weak acid or base taken orally will become protonated in the stomach:
A- + H+ > AH
B + H+ > BH+
Most oral drugs are weak acids, because protonated acids are not ionized and are therefore readily absorbed

Question 34

Degree of ionization may differ on different sides of membrane. How does this affect where drugs accumulate? What is ion trapping?

Answer 34

Degree of ionization may differ on different sides of membrane

Drug accumulates on side of membrane where ionization is highest (i.e., where bases are bound to protons [BH+] and where acids are not bound to protons [A-])

> called pH trapping or “ion trapping”
• Basic drugs accumulate in acidic fluids
• Acidic drugs accumulate in basic fluids
-Tissue pH determines degree of ionization

Question 35

when are acidic and basic drugs absorbed, respectively, in regards to protonation?

Answer 35

Acidic drugs are readily absorbed when protonated (AH) whereas basic drugs are better absorbed when unprotonated (B)

Question 36

what is the ratio of protonated to unprotonated drug if pH = pKa? How does this change as the pH and pKa begin to differ?

Answer 36

When pH = pKa, the ratio of protonated to unprotonated drug is 1:1. This
ratio changes by a factor of ten for each unit difference between pH and pKa.