Absorption and distribution of drugs

Question 1

What is covered by PD?

Answer 1

PD covers:
1. drug-receptor interaction
2. receptor conformation and activation
3. interactions
4. structure of 4 receptor families
5. immediate effect of some receptors
6. receptor coupling
7. signal transduction
8. cellular response leading to pharmacological effect

Question 2

What is covered by PK?

Answer 2

PK covers everything that happens to drugs before it is bound to the receptor. It studies ADME (Absorption, distribution, metabolism, and excretion).

Question 3

Describe routes of administration.

Answer 3

Routes of administration:
1. systemic - in the circulation
a. enteral (oral, rectal, sublingual)
b. parenteral - bypass GI system (inhalation and injection - IV, IM, SC, IT)
2. local - to a specific site of the body
a. skin, transdermal, intraocular, intranasal

Question 4

Classification of dosage form.

Answer 4

1. route of adminitration
2. physical form of drug (solid, semi-solid, liquid, gases)

Question 5

Inhalation.

Answer 5

It is used for volatile and gaseous anesthetics. The lung serves as both a site of administration and elimination. But also there is minimum systemic effect. Glucocorticoids and bronchodilators. Include dry powder, liquid sprays, and aerosol. The size of particles is between 5 to 7um.

Question 6

Oral.

Answer 6

1. solid dosage forms
   a. tablets
   b. capsules
   c. granules
   d. sublingual tablets
   e. buccal tablets
2. liquid dosage forms
   a. solutions
   b. suspensions
   c. emulsions

Question 7

Topical.

Answer 7

1. semi-solid dosage forms (ointments, creams, lotions)
2. sprays
3. transdermal
4. patches

Question 8

Nasal, ocular, and otic.

Answer 8

Nasal:
1. spray
2. drops
Ocular:
1. drops
2. ointments
3. contact lens
4. implants
Otic:
1. topical
2. intracochlear
3. intratympanic

Question 9

Parenteral. What is a bolus injection? What are the rate limiting factors?

Answer 9

1. IM
2. SC
3. IV
4. ID
   Bolus injection rapidly produces a high concentration of the drug, first in the right heart and pulmonary vessels and then in the systemic circulation.
   Rate limiting factors:
5. diffusion through the tissue
6. removal by local blood flow

Question 10

Rectal/vaginal.

Answer 10

This route of administration can be useful in patients who are vomiting or are unable to take medications by mouth.
a. suppositories
b. tablets
c. enema
d. creams and gels
e. foams

Question 11

What is absorption?

Answer 11

Movement of the drug into the bloodstream making the drug available for distribution on the target tissues and organs.

Question 12

Route of oral administration.

Answer 12

Administrated drug first goes into the stomach (GIthenthat it travels to the small intestine from where it goes from the hepatic portal vein into the liver where it is metabolite to be transferred into the systemic circulation.

Question 13

Factors that affect absorption.

Answer 13

Drug-related:
1. size and shape
2. lipid solubility
3. ionization state
4. formulation
Route of absorption-related

Question 14

How does the drug lipophilicity affect absorption?

Answer 14

Drugs with high solubility are generally absorbed more quickly than those with low solubility. This is because highly soluble compounds can dissolve rapidly in the fluids lining the gut, allowing them to pass through the walls of the gastrointestinal tract more readily. Non-polar molecules dissolve freely in membrane lipids and diffuse readily across cell membranes. The number of molecules crossing the membrane per unit area in unit time is determined by the permeability coefficient, P, and the concentration difference across the membrane. Thus, two physicochemical factors contribute to P, namely solubility in the membrane and diffusivity, which is a measure of the mobility of molecules within the lipid and is expressed as a diffusion coefficient.

Question 15

How does the drug size
affect absorption?

Answer 15

Small molecules tend to penetrate membranes more rapidly than larger ones. Only materials that are relatively small and nonpolar can easily diffuse through the lipid bilayer.
There are four main ways by which small molecules cross cell membranes:
1. by diffusing directly through the lipid;
2. by combination with a solute carrier or other
membrane transporter;
3. by diffusing through aqueous pores formed by special membrane glycoproteins (aquaporins) that traverse the lipid;
4. by pinocytosis.
Two classes of proteins that mediate facilitated diffusion are generally distinguished:
1. carrier proteins (carrier proteins bind specific molecules to be transported on one side of the membrane. They then undergo conformational changes that allow the molecule to pass through the membrane and be released on the other side)
2. channel proteins (channel proteins form open pores through the membrane, allowing the free diffusion of any molecule of the appropriate size and charge)
3. endocytosis (involves engulfment of a drug by the cell membrane and transport into the cell by pinching off the drug-filled vesicle, vitamin B12)
4. exocytosis (neurotransmitters)

Question 16

Specialized transporters.

Answer 16

Specialized transport mechanisms regulate the entry and exit of physiologically important molecules, such as sugars, amino acids, neurotransmitters, and metal ions. They are broadly divided into:
1. SLC transporters
a. OCT
- dopamine and choline
- uniporters
- OCT (present in hepatocytes)
- OTC2 (present in proximal renal tubules, concentrates drugs such as cisplatin in these cells resulting in its selective nephrotoxicity)
b. OAT
- responsible for the renal secretion of urate, prostaglandins, several vitamins, and p-amino hippurate, and for drugs
2. ATP-binding cassette (ABC) transporters
- P-glycoproteins which belong to the ABC transporter superfamily, are the second important class of transporters and are responsible for multidrug resistance in cancer cells
- they play an important part in the absorption, distribution, and elimination of many drugs
- are present in renal tubular brush border membranes, in bile canaliculi, in astrocyte foot processes in brain microvessels and in the gastrointestinal tract

Question 17

How does the drug ionization affect absorption?

Answer 17

The pH of the environment where drug absorption happens can affect ionization and absorption. Non-ionized drugs can pass cell membranes while ionized drugs cannot. For example, acidic drugs are more easily absorbed in an acidic environment (stomach) whereas basic drugs are in the small intestine. Ionization and membrane permeability affect both the rate of permeability and steady-state distribution between aqueous compartments. Most drugs are either weak acids or bases (formulas). The ionization state varies with pH according to the H-H equation.

Question 18

How does the formulation affect the absorption?

Answer 18

Tablets and capsules have slow absorption because they have to be disintegrated and dissoluted before they enter circulation. Powders and suspensions have faster rates of absorption because before entering circulation they have to be dissoluted. However, solutions have a faster rate because they immediately enter circulation.

Question 19

How does the area of the absorbing surface affect absorption??

Answer 19

The larger the surface area the better the absorption. Lungs 75m2 and intestine 260-300m2.

Question 20

How does the blood flow affect absorption?

Answer 20

When we have poor blood flow absorption is slow whereas when we have rich blood flow absorption is fast.

Question 21

Which factor affects the absorption of orally taken drugs?

Answer 21

1. presence of food
   - delay gastric emptying time
   - alter GI pH
   - stimulate bile flow
   - increase splanchnic blood flow
   - physically interact with drug
   - 1h before or 2h after
   - increase rate of absorption, overdose effect
2. gastric emptying
   - food in the stomach
   - viscosity of stomach content
   - size of tablet or capsule
   - sedation, mobility
   - abdominal compartment pressure
   - gastric perfusion
   - autonomic and hormonal activity
   - anticholinergic drugs
3. gastrointestinal motility
4. pH level
5. digestive enzymes
   - carbohydrates (amylase, maltase, lactase. sucrase-isomerase)
   - proteins (pepsin, trypsin, peptidase)
   - fats (lipase)
   To bypass first-pass metabolism we use a sublingual or buccal route of administration, the drug is absorbed by oral mucosa.

Question 22

Which factors affect the absorption of the rectal route of administration?

Answer 22

1. enteral route of administration
2. safe but not comfortable method of delivery
3. has both local and systemic effect
4. rapid absorption
5. 50% enters bloodstream directly
   Useful for drugs that:
   a. undergo high hepatic first-pass metabolism
   b. have limited absorption in upper GIT
   c. degradable or unstable in GIT
   d. cause irritation of gastric mucous
   e. cannot be formulated differently
   f. localized effect in the rectum

Question 23

Sublingual/buccal route of administration.

Answer 23

1. avoid first-pass metabolism
2. enteral route

Question 24

Parenteral route of administration.

Answer 24

1. help of another person
2. avoid first-pass metabolism
3. uncomfortable

Question 25

What is bioavailability?

Answer 25

Fraction (%) of the adminitsrated dose that reaches the systemic circulation.

Question 26

Methods to modify the rate of absorption.

Answer 26

1. The addition of adrenalin to a local anesthetic reduces the absorption of the anesthetic into the general circulation, prolonging the effect.
2. Insulin zinc suspension long-acting form.
   If blood concentration of both oral and parenteral forms are equal then the rate of elimination also becomes equal.

Question 27

What is distribution?

Answer 27

Movement of drug from bloodstream to extracellular fluid or tissue.

Question 28

Body water compartments.

Answer 28

50-70% H2O
1. extracelullar fluid (1/3)
- plasma 20%
- interstitial fluid 80%
- lymph
2. intracellular (2/3) fluid - sum of fluid contents of all cells in the body
3. transcellular - CSF, lymph, bile, intraluminal GI fluid, intraocular.
The equilibrium pattern of distribution depends on:
a. permeability across tissue barrier
b. binding with compartments
c. pH
d. fat:water partition

Question 29

Factors affecting distribution.

Answer 29

1. lipid solubility
2. blood flow
3. protein binding
   - the main determinants:
   a. no. of available binding sites
   b. no. of drug molecules
   c. association constant of drug and binding site
   d. lipophilicity and pKa of drug
   e. resemblance to endogenous ligands of the transport protein
   - environment conditions:
   a. pH
   b. endogenous ligands
   c. protein level
   d. T
   - proteins and blood components:
   a. albumin
   b. lipoproteins
   c. globulin
   d. haemoglobulin
   e. RBC membrane
4. capillary permeability
   *blood-brain barrier
   *placenta barrier
   *testicular barrier

Question 30

What is the volume of distribution?

Answer 30

Shows where in the body the drug is accumulated. Vd is volume of solvent that would contain the total body content of the drug at a conc. equal to the measured plasma conc.
The Vd represents the volume of blood or body fluids that would have the same concentration of the drug as is measured in the plasma.

Question 31

Examples.

Answer 31

1. Heparin
   - goes into the bloodstream
   - large size
   - charged
   - plasma protein bound
   - Vd=4l
2. Glibenclamide
   - goes into the bloodstream and extracellular fluid
   - smaller size
   - hydrophilic
   - low plasma protein bound
   - Vd=14l
3. Vd = volume of total body fluid
   *ethanol, aspirin
   - small size
   - lipophilic, non-polar
   - not plasma bound
4. Vd > total body fluid
   - goes directly to the tissue