drug absorption

Question 1

describe routes of drug administration and explain the rate and extent of drug absorption

Answer 1

intravascular:
1. iv bolus injection (parenteral)
(immediate and complete absorption
rate and extent dependent on dose and conc)
2. iv infusion (parenteral)
(immediate and complete absorption
rate and extent dependent on dose and conc and rate of injection can inject large volumes over time)

extravascular:
1. subcutaneous (parenteral)
(rate and extent depend on blood flow to injection site, dose and solubility. suitable for poorly soluble, unsuitable for large volumes)

2. intramuscular (parenteral)
   (good for modified release can cause tissue damage. rate and extent depend on blood flow to injection site, dose and solubility)
3. intradermal (parenteral)
   (local exposure to dermis of skin used for allergy tests)
4. intrathecal (parenteral)
   (into csf, bypasses BBB, need good sterility)
5. oral (enteral)
   (slow and variable absorption, less predicatble. rate and extent dep. solubility, stability, presence of food in the stomach, acidity of stomach)
6. buccal/sublingual (enteral)
   (rapid absorption for lipophilic, avoid GIT degredation)
7. rectal (enteral)
   (variable absorption avoid GIT degradation)
8. inhalation/intranasal
   (particle size important, rapid absorption rate and extent depends on depth of inhalation dose and solubility.)
9. topical
   (rate and extent of absorption depend on the dose, the solubility of the drug, and the thickness of the tissue.)

Question 2

describe anatomy and physiology of GI tract that have PK implications

Answer 2

stomach:
parietal cells release HCL (ACIDITY breaks down substances, acidic drugs are not ionized here, aids absorption ex: aspirin and ethanol)
chief cells release pepsinogen and gastric lipase (protein and fat digest)
G cells secrete gastrin, interacts with parietal cells HCL decrease

folds for high SURFACE AREA (gastric pits)

small intestine:
duodenum
major site of PASSİVE DİFF.
RİCH BLOOD SUPPLY; better absorption.
PROTEOLYTİC ENZYMES
pH increases due to ducts from pancreas and gall bladder 6-6.5

jejunum
vili to increase SURFACE AREA, better absorption.

ileum
high bicarbonate content, dissolves acidic drugs fats and hydrophobic drugs (7-8)

A longer TRANSIT TIME can increase the amount of time a drug is in contact with the absorptive surface, leading to greater absorption.

drug absorbed into epithelial cells with phospholipid bilayer cell membrane. (repels charged lipophobic molecules)
metabolising enzymes in GIT:
CYP (gut wall and liver)
UGT (glucoronic acid added)
SULT (sulphur added)
cause first pass effect (not all of drug absorbed)

Question 3

describe the mechanism of oral drug absorption

Answer 3

1. disintegration into small particles
   (usually rapid, not rate limiting)
2. dissolution into solvent : mass of solute that dissolves in volume of solvent
   (rate limited if poor water solubility)
3. absorption through membranes
   transcellular (in cells)
   → passive dif. ,
   depends on conc. gradient, Log P needs to be high, pKa needs to be low not ionised, hydrogen bonding within molecule, small size
   → carrier mediated (active and facilitated) ,
   facilitated has minor role in absorption, has structural selectivity,
   active prone to saturation and needs energy, against conc., transporter selective, efflux and uptake transp. can impede or enhance.
   → endocytosis
   paracellular (between cells)
   needs to be low MW and hydrophilic. less surface area more transcellular absorption

Question 4

explain the barriers to oral drug absorption

Answer 4

• first pass metabolism
  (gut and hepatic metabolism via CYP3A4 or UGT before entering systemic circulation),
  -luminal degradation
  via enzymes or gut wall microbes
  -Transporters
  -Solubility and permeability

double peak:
-enterohepatic recirculation (glucoronidation and degluconoridation)
-variability in gastric emptying
- local action of drug (if it reduces gastric motility)
-mucus layer decreases penetration

Question 5

discuss role of transporters and enzymes in process of oral drug absorption

Answer 5

influx transporters:
on apical membrane transport drug to blood: PEPT1, OATP, MCT1 (SLC FAMİLY)
on basal membrane transport drug to lumen: OCT 1

efflux transporters:
on basal membrane transport drug to blood: ABCC
on apical membrane transport drug to lumen: (ABC FAMİLY) ABCB1/ P-gp

enzyme: CYP3A4 (CYP450 family), liver and intestinal epithelium

Question 6

list and explain factors affecting oral drug absorption

Answer 6

1. physiological factors
   gastric emptying. slow emptying reduces absorption
   GIT motility, increased reduces absorption
   DME and transporters
   pH, weak acids need to be in more acidic weak bases need to be in more basic to be absorbed (absorbed when unionised)
2. physiochemical properties of the drug
   molecular size
   lipopholicity
   pKa
3. formulation dependent factors e.g., slower absorption of pill vs liquid, certain salts are more soluble
4. food effect

Question 7

describe the pharmaceutical consideration for oral drug absorption

Answer 7

1. rapid dissolution
2. controlled release
3. enteric coating

class 1: high solubility (drug dissolving in gastric medium) and permeability (permeation through gut wall)
class 2: low solubility high permeability
class 3: high solubility low permeability
class 4: low solubility and permeability

Question 8

explain drug absorption through the skin

Answer 8

Transepidermal or appangeal

Absorbed into the vasculature in the viable epidermis, dermis, or subcutis + deep tissue.

Transepidermal can be transcellular (diffusion through the cells), or extracellular.

Appangeal absorbes through hair follicles and/or sweat glands.