Pharmacokinetics

Question 1

1. What are the 4 primary mechanisms of drug permeation?

Answer 1

1. Aqueous diffusion (paracellular pathway)
2. Lipid diffusion (transcellular pathway)
3. Special carriers
4. Endocytosis and exocytosis (transcytosis)

Question 2

2. What is aqueous diffusion?

Answer 2

The passage of drugs through intracellular pores (b/t cells) – this is important esp in the kidney, but NOT in the BBB where there are continuous tight junctions that restrict the paracellular diffusion of the drugs

Question 3

3. What is lipid diffusion?

Answer 3

Most drugs are weak acids or bases and therefore contain ionized and unionized forms of drugs. In the unionized form of a drug it presents a very lipophilic state and therefore allows for easy diffusion across the cell membrane of the cells. The ionized form of a drug is incapable of diffusing across the lipophilic cell membrane. This process is governed by Fick’s law.

Question 4

4. What is the role of special carriers in drug absorption?

Answer 4

Drugs that are too large to move paracellularly and not unionized therefore cannot move through the membrane can move through the membrane through protein transporters located in the membrane. Examples of these molecules include peptides, amino acids, and glucose. Drugs resemble these molecules which is why they can also use them as carriers. These carriers can be active or facilitated. These transporters, unlike passive diffusion, can be inhabitable and saturable.

Question 5

5. What is transcytosis?

Answer 5

Transcytosis occurs when molecules are too large for transporters. Therefore these drugs can be endo- and exocytosed. Once endocytosed, the vesicle can be broken down in the cytosol or make its way to the other side of the cell.

Question 6

6. Define absorption.

Answer 6

Transfer of a drug from its site of administration to the bloodstream. The rate and efficiency of a drug depends on the route of administration. Ex. IV delivery has complete absorption (high bioavailability) because it is all delivered to the systemic circulation.

Question 7

7. What are the enteral routes of drug administration?

Answer 7

1. Oral → most convenient, but less effective and slower. Drugs administered in this manner will undergo the first pass effect (metabolism) where the drug will be metabolized in the gut wall and liver before reaching the circulation.
2. Sublingual → drug is placed under the tongue allowing it to be absorbed in to the capillary network bypassing the intestine and liver metabolism which would inactivate the drug
3. Rectal → partial avoidance of 1st pass metabolism but there is a high rectal mucosa irritation occurence and absorption is erratic and incomplete

Question 8

8. What are the parenteral routes of drug administration?

Answer 8

1. Intravenous → instantaneous and complete absorption but could be the most dangerous due to instant effect
2. Intramuscular → direct injection in to the muscle that has a quicker effect compared to oral drugs
3. Subcutaneous → injection under skin, but not in the muscle, slower absorption than intramuscular
4. Intradermal → drug injected in to dermis layer of skin (ex. PPD)

Question 9

9. Discuss other routes of drug administration (oral inhalation, nasal inhalation, intrathecal/intraventricular, topical, transdermal).

Answer 9

Oral inhalation → generally used for respiratory disease due to delivery closest to desired site of action
Nasal inhalation → agents include a-adrenergic agonists for nasal decongestion and desmopressin for diabetes insipidus
Intrathecal/Intraventricular → Used to administer drugs directly to the CSF (ex. amphotericin B in cryptococcal meningitis)
Topical → used for local effect (ex. Clotrimazole is a cream applied to treat dermatophytosis on the skin or Tropicamide(cyclopentolate) applied to the eye for dilation)
Transdermal → drug applied to skin via patched and is usually used for sustained delivery of drugs

Question 10

10. What factors influence drug absorption?

Answer 10

1. pH
2. surface area of absorption site
3. blood flow to absorption site
4. contact time at absorption surface (ex. with diarrhea the drug is not absorbed well because of increased intestinal emptying)
5. P-glycoprotein

Question 11

11. How does pH affect drug absorption?

Answer 11

Most drugs are weak acids or bases in solution therefore can be present in ionized and unionized states. The nonionized state is liposoluble diffusing through membrane, but the ionized state is unable to penetrate through membrane due to low liposolubility.
Weak acid: AH←→ A- + H+
Weak base: BH+ ←→ B + H+
**uncharged forms move through membrane → protonated form of weak acid moves through membrane (liposoluble) and the neutral/unprotonated form of the weak base is more liposoluble (moves through membrane)
Henderson-Hasselbalch → pH-pK = log ([unprotonated]/[protonated])

Question 12

12. What is ion trapping?

Answer 12

Ion trapping involves the manipulation/adjustment of urine pH to make a drug trapped in the ionized state therefore preventing its reabsorption. This most commonly occurs in the kidney/glomerulus due to excretion in the urine. Weak acids are excreted faster in alkaline urine and weak bases are excreted faster in acidic urine.
Ex. pt overdose with weak acid drug therefore increase excretion by alkalizing the urine by giving sodium bicarb
Ex. weak base drug excretion can be accelerated by acidifying the urine by giving administering ammonium chloride

Question 13

13. What are rules of the HH equation?

Answer 13

1. when pH=pK, then [unprotonated]=[protonated]
2. for each unit pH is above pK the [unprotonated] will by 10x the [protonated]
3. for each unit pH below the pK [protonated] will be 10x [unprotonated]

Question 14

14. How does surface area effect drug absorption?

Answer 14

Increase surface area → increase drug absorption
Amt of villi/microvilli in the ileum increase surface area which is much higher than the stomach. Therefore the rate of absorption in the intestines is much greater than the stomach even if the drug is predominantly ionized in the intestines and largely nonionized in the stomach. Other factors such as food effects stomach absorption and slower gastric emptying. Increase absorption with increased gastric emptying (medicine on empty stomach).

Question 15

15. What is the role of the P-glycoprotein?

Answer 15

P-glycoprotein (multidrug resistance protein 1 [MDR1]). This is a multidrug transmembrane transporter protein located in the liver, kidney, intestines and brain capillaries. This transporter is responsible for transporting drugs across the cell membrane. This transporter reduces drug absorption and is associated with multidrug resistance.
Liver → into bile for elimination
Kidney → into urine for excretion
Intestines → into intestinal lumen
Brain capillaries → back in to the blood decreases drug access to the brain

Question 16

16. What is the bioavailability of a drug?

Answer 16

The bioavailability is the fraction of drug administered that reaches the systemic circulation. The bioavailability of an IV administered drug is 100%. To measure bioavilability, graph the IV admin of a drug and the oral admin of a drug.
F (bioavailability) = [AUC(oral)/AUC(IV)]*100
AUC = area under the curve
y-axis = plasma concentration of a drug
x-axis = time after administration

Question 17

17. What is a drug formulation?

Answer 17

The additives and drug combined that effects the degree of absorption of the drug and how quickly it disintegrates in the GI prior to absorption.

Question 18

18. What factors affect drug bioavailability?

Answer 18

1. drug formulation
2. chemical instability – pH of gastric contents can make penicillin G unstable, gastric enzymes can break down insulin
3. food and drug interaction – bile acids can reduce absorption, laxatives can reduce absorption, high fiber can prevent drug by being absorbed by binding it
4. first-pass hepatic metabolism
5. drug solubility – hydrophilic drugs are poorly absorbed b/c they can’t cross membrane nor gain access to the surface of cells, we want drugs to by HYDROPHOBIC with some solubility
6. P-glycoprotein – pumps drug out of the gut wall cells back into the gut lumen decreasing bioavailability

Question 19

19. What is the pharmaceutical equivalence and bioequivalence?

Answer 19

Pharmaceutical equivalence → contain same active ingredients in identical concentrations, dosage form, route of administration
Pharmaceutical bioequivalence → concentration-time plots are superimposable and one can be safely replaced by the other