G1 Absorption and distribution

Question 1

what route of administration has no absorption step?

Answer 1

intravenous injection

Question 2

what does the speed and extent of drug absorption depend on?

Answer 2

• the properties of the drug molecule
• the environment at the site of administration

Question 3

what do the physicochemical properties of drug molecules determine? what physiochemical properties are we referring to?

Answer 3

• rate of diffusion
• relative lipid or aqueous solubility
• diffusion constant
• partition coefficient (how much drug is soluble in aqueous and lipophilic phases)

Question 4

state 2 major factors that go towards the rate of diffusion and solubility of drug molecules

Answer 4

• charge or polarity
• size

Question 5

what state will molecules cross lipid bilayers by passive diffusion in?

Answer 5

only uncharged (unionised form)

Question 6

state the 2 equilibrium equations of ionisation and unionisation of weak acids and bases

Answer 6

A represents acidic drugs
B represents basic drugs

Question 7

what does ionisation state depend on?

Answer 7

• pH of environment
• pKa of drug

Question 8

what is pKa?

Answer 8

pH at which 50% of molecules are in each state (unionised and ionised)

Question 9

what is the pH in the mouth? what percentage of drugs are ionised here (acidic and basic)?

Answer 9

• 7.4
• acidic drug: 99.5% ionised
• basic drug: 0.5% ionised

Question 10

what is the pH in the stomach? what percentage of drugs are ionised here (acidic and basic)?

Answer 10

• 1.5
• acidic drug: 0% ionised
• basic drug: 100% ionised

Question 11

what is the pH in the small intestine? what percentage of drugs are ionised here (acidic and basic)?

Answer 11

• 5.3
• acidic drug: 40% ionised
• basic drug: 60% ionised

Question 12

theoretically, where should most acidic drugs be absorbed and why? why is this not the case in reality?

Answer 12

theoretically:
- 100% unionised in stomach due to low pH
- should be absorbed the most in the stomach due to being all unionised

reality:
- most drugs are absorbed in the small intestine
- due to high surface area and with a still high proportion of unionisation

Question 13

what must drugs do to enter a blood vessel lumen?

Answer 13

cross one or more membrane barriers

Question 14

what factors affect drugs crossing membrane barriers to enter blood vessel lumen?

Answer 14

• structure of barriers (epidermal / mucosal layer, capillary structure)
• concentration gradient across membrane (influenced by blood flow)
• surface area available for transfer
• residence time at membrane
• first pass metabolism

Question 15

describe what happens when drugs are given orally in terms of first pass metabolism

Answer 15

• the hepatic system takes the drugs to the liver before it enters the systemic circulation
• some of the drug is metabolised by the liver enzymes so the bioavailability of the drug is reduced

Question 16

describe bioavailability and how it is determined

Answer 16

• a measure of how much drug is absorbed and reaches the systemic circulation
• normally a fraction or percentage
• determined by comparison of a dose delivered by the oral route to the same dose delivered by intravenous injection

Question 17

in the image, what are tmax and Cmax?

Answer 17

• tmax: time taken to reach maximum concentration
• Cmax: maximum concentration reached

Question 18

describe the variations in drug absorption across the lifespan

Answer 18

gut maturation isn’t complete in newborns
- GIT is still developing and changing
- when prescribing, this must be considered

intestinal transit time is shorter in newborns and longer in the elderly

gastric pH is reduced in newborns and elderly
- varies in the first few years of life

Question 19

what can plasma proteins act as? give an example of a plasma protein that does this

Answer 19

• carriers for poorly soluble metabolites
• eg. serum albumin

Question 20

explain plasma protein binding of drugs

Answer 20

• plasma proteins (eg. serum albumin) act as carriers for poorly soluble metabolites
• many drugs bind to these carrier proteins and are transported around the circulation
• the binding is reversible (so eg. fatty acids are delivered to cells effectively despite lack of solubility)

Question 21

what do binding interactions with plasma proteins influence?

Answer 21

strongly influence drug pharmacokinetics

Question 22

describe the process of drug binding to plasma proteins

Answer 22

binding removes drug from free solution
- drug no longer free to diffuse into surrounding tissue
- binding proteins act as a reversible ‘sink’ which increases amount of drug in blood
- aids absorption and transport of drug
- slows elimination
- binding proteins are normally in excess of active drug concs, but saturation can cause non-linear dosing effects

Question 23

what can very high affinity plasma protein binding cause?

Answer 23

can restrict the drug to the plasma and it won’t reach tissues

Question 24

in regards to plasma proteins, how can drug interactions be caused?

Answer 24

if drug compete for binding sites on plasma proteins

Question 25

which is available for distribution: free or bound drug?

Answer 25

free bound drug will remain in the plasma with plasma protein

Question 26

describe and explain the dynamic equilibrium between bound and free drug

Answer 26

- thermodynamic motion leads to chance collision - electrostatic binding forces can be overcome by thermal energy - 90% of drug bound is equivalent to one molecule being bound 90% of the time - drug with lower affinity to plasma protein will be free so more available for absorption (leads to higher therapeutic effect)

Question 27

describe continuous capillaries and what their structure means for aqueous and lipophilic molecules

Answer 27

- they have leaky junctions between endothelial cells - aqueous molecules can cross these junctions - lipophilic molecules can cross the cells (they don't need gaps)

Question 28

describe fenestrated capillaries and what their structure means for aqueous molecules

Answer 28

- they have large pores - aqueous molecules can cross these and be distributed

Question 29

describe transcytosis

Answer 29

- brings proteins and macromolecules across endothelium - some vesicles may fuse to create temporary channels

Question 31

what is meant by teratogenic?

Answer 31

leads to birth defects in baby

Question 32

what is meant by embryotoxic?

Answer 32

leads to miscarriage

Question 33

describe what kinds of drugs have access to the foetus via the placenta and which do not

Answer 33

- lipophilic drugs have ready access - drugs with high plasma protein binding affinity do not have access

Question 34

describe the diffusion of drugs into breastmilk

Answer 34

- alveolar apical cells form a tight-junction limited lipid barrier between capillaries and alveolar lumen - diffusion into milk therefore limited by lipophilicity and size

Question 35

describe drug accumulation in tissue depots

Answer 35

- drug can accumulate in binding sites or intracellular organelles - may be target site, other proteins, lipid compartments etc. - time course for accumulation depends on perfusion of organ system and drug pharmacokinetics - adipose tissue is a major reservoir for lipophilic drugs - redistribution can occur over time

Question 36

describe adipose tissue

Answer 36

- located in skin (subcutaneous), around internal organs (visceral), breasts and in bone marrow - composed of adipocytes: cells with large intracellular vacuoles filled with lipids - lipid soluble drugs can accumulate in this reservoir - increase in adipocyte size (and maybe number) with obesity

Question 37

what different compartments are drugs distributed around the body in?

Answer 37

- extracellular fluid (plasma, interstitial fluid, lymph) - intracellular fluid (cell contents) - transcellular fluid (CSSF, peritoneal, intraocular, synovial etc.) - fat - bound to protein

Question 38

what is volume of distribution?

Answer 38

theoretical volume of plasma that would accommodate total drug amount at the measured plasma concentration

Question 39

volume of plasma fluid

Answer 39

3 L

Question 40

volume of extracellular fluid

Answer 40

12 L

Question 41

volume of total body water

Answer 41

40 L

Question 42

what does a volume of distribution over 40 L indicate?

Answer 42

some storage of drug in tissues

Question 43

what does a volume of distribution under 15 L indicate?

Answer 43

drug is largely restricted to plasma and interstitial fluid

Question 44

variation in distribution throughout lifespan

Answer 44

body composition changes with age - higher fat : lean tissue ratio in infants - obesity increases with age - relative volume of fluid compartments varies (volume of distribution tends to be higher in infants) - pregnancy adds placental and breastmilk compartments - plasma protein synthesis in the liver declines with age - renal function affects tissue fluid volumes (oedema and diuretic use)