Lec 2-Absorption

Question 1

Switching formulations

Answer 1

• Morphine- terminal illness, cancer patients IV morphine
• Morphine- end of life care= oral morphine
• the dosage for the different routes can be large

Question 2

Drug absorption routes

Answer 2

• Absorption
  
  • Oral
  • Topical
  • Inhaled
  • IM
  • SC
• Non- absorbed
  
  • IV- no absorption due to dose being delivered directly into circulation- 100% = F

Question 3

Drug absorption- oral dose

Answer 3

• Absorption processes typically can delay the clinical effect of the drug as a result of the drug needing to go from the site of administration to the site of action

Question 4

Drug absorption- transdermal/topical

Answer 4

• Absorption processes typically can delay the clinical effect of the drug, as a result of the drug needing to go from the site of administration to the site of action

Question 5

Drug absorption- IM/SC

Answer 5

• Absorption processes typically can delay the clinical effect of the drug, as a result of the drug needing to go from the site of administration to the site of action
  
  • Still has many absorption barriers

Question 6

Drug absorption processes

Answer 6

• Solid => Disintegration => Dissolution => Absorption
• These steps are Prerequisites to absorption and at each stage of this process we can lose large amounts of our initially dosed drug
• Bioavailability (F) means the extent to which the active moiety is absorbed from a drug product and becomes available in the systemic circulation
• Dissolution is the process which is the slowest especially if the drug is poorly soluble, to overcome this we can make the drug into the salt form (which is ionised therefore more soluble)
• Absorption is characterised by the bioavailability and the absorption rate constant

Question 7

Drug absorption- sites

Answer 7

• Epileptic drugs- the target site is in the brain, there are therefore many different absorption barriers to cross from GI => circulation => brain
• Capillaries are one of the main absorption barriers (cell membrane- lipid bilayer)
• The site of drug action typically intracellular
• Absorption is a pre-requisite for site-targeting and clinical effect
• All tissues/organs have a biological membrane/barrier which drugs must be able to transverse to reach their target sites and is highly dependant on lipophilicity of the drug
• A barrier in the capillary/blood vessels is one of the main barriers in the body (cell membrane lipobilayer)
• NB- most of the barriers in the body are lipobilayers

Question 8

Pharmacokinetic- drug properties

Answer 8

• Specific properties of the drug can have a significant effect in influencing how quickly or slowly a drug is able to partition across cell membranes
• Most drugs have to be non-ionised and lipophilic to cross membranes
• Factors involved in absorbing a chemical:
• Physiochemical properties
  
  • Hydrophilic/phobic
  • Ionized/no-ionized/Weak acid or base
  • Molecular Weight (Should be below 500)

Question 9

Pharmacokinetics- drug properties oral dose Lipophilicity

Answer 9

• Lipophillic (LogP)
• Be lipophillic meaning it will partition into the lipid bilayer
• Absorption rate is usally quicker

Question 10

Drug properties- ionisation

Answer 10

• Non-ionised drugs are absorbed far quicker
• This is because the outside of the lipid bilayer is charged meaning that ionised molecules are repelled
• Non-ionised drug are uneffected

Question 11

Drug absorption pathways

Answer 11

• Paracellular route- Between cells = Diffusion
• Transcellular route- through cells
  
  • Passive= diffusion
  • Carrier-mediated = active facilitated
  • Endocytosis= receptor mediated

Question 12

Paracellular (passive diffusion)

Answer 12

• Passive process
• Very low MW drugs pass through
• Dependant on drug properties (Ionisation state, pH)
• The lipid-like membrane acts as a filter letting through only very small dissolved drug particles
• Concentration depends on and enhances the process

Question 13

Transcellular (passive diffusion)

Answer 13

• Drugs crossing cells via diffusion
• Must be hydrophobic drug particles
• Hydrophobic= dissolution issues
• Concentration dependent, pH and ionisation state of drug
• LogP (lipophilicity) is important in determeningthe extent of permeation

Question 14

Pharmacokinetics- transcellular (carrier mediated transport)

Answer 14

• Carrier-mediated system
• Like a transporter pump
• Requires ATP
• Enzyme therefore prone to Saturation
• System cane exist in Uptake (in) or in Efflux (out) state
• Drug-drug interaction can compete for the transporter
• Specific transporters exist for endogenous substances in the body
• One reason chemotherapy doesn’t work in some people is that a tumour will pump out the chemotherapy drug (efflux)

Question 15

Transcellular- receptor-mediated endocytosis

Answer 15

• Drug will bind to a receptor
• Drug is encolsed into a vesicle
• Then delivered to the other side
• Very specific
• Vaccines and other proteins- due to there size

Question 16

Pharmacokinetic- graphic

Answer 16

• The route of administration plays a role in the type of profile we get
• The profile tells us about how the clinical outcome

Question 17

Drug ionisation and pH

Answer 17

• The pH and ionisation of drugs is Key in their absorption
• Ionised molecules cannot cross membranes
• Only unionised molecules can pass

Question 18

pH

Answer 18

• pH varies across the body
  
  • The stomach is acidic- intestinal fluid pH= 1.2
  • Blood is neutral- Blood pH= 7.4
• A weak acid drug, HA will exist as:
  
  • The Unionised form within the intestinal fluid
  • The Ionised form within the blood

Question 19

Henderson-Hasselbach equation

Answer 19

ACID

• pH- pKa= Log (^Ionised/_Unionised ) - NB- ACID has an I so Ionised is on top

BASE

• pH- pKa = Log(^Unionised/_Ionised)
• Used to work out whether the drug is ionised or unionised
• Not in the equation sheet- Must learn

Question 20

Henderson-hasselbach- example

Answer 20

• Diazepam pKa = 3
• In stomach pH=1.2
• In Blood pH= 7.4
• The drug exists mainly in the Unionised state the ratio will be Bottom heavy
• If the drug exists mainly in the ionised state the ratio will be top heavy

Question 21

How does this affect absorption

Answer 21

• Excess HA (unionised) exists thus the concentration gradient sends it into the blood
• Excess A- (ionised) exists thus it cannot go back to the intestinal fluid
• Overall absorption is increased

Question 22

Weak bases: ionisation can be a disadvantage

Answer 22

• There is a pH difference between intestinal fluid and blood
• A weak base drug BH+ will exist as
• Ionised in intestinal fluid (Limited absorption)
• Unionised in the blood (diffusion back into the stomach)

Question 23

Graphically

Answer 23

• We have to give a much higher dose with oral medication due to
  
  • Bioavailability: first pass metabolism; poor absorption (excreted); disintegration; dissolution; destruction (acidic)
• Must give a higher dose for oral than IV
  
  • Poor absorption
  • F
    *