Absorption of Drugs

Question 1

Define bioavailability. What is the relative bioavailability of oral vs IV ?

Answer 1

Fraction of unchanged drug that reaches the systemic circulation

IV injection gives 100% bioavailability
Oral intake much lower bioavailability due to being vulnerable to enzymes, acidic environments, liver metabolism before reaching systemic circulation.

Question 2

How may we calculate percent bioavailability of an oral drug ?

Answer 2

% Bioavailability oral drug = (Area under curve for oral drug / Area under curve for intravenous drug) x 100
in graph showing bioavailabilities of IV and oral injections.

Question 3

Define generic and therapeutic substitutions.

Answer 3

Generic substitution occurs when a different formulation of the same drug is substituted. All generic versions of a drug are considered by the licensing authority to be equivalent to each other and to the originator drug (I.E. SAME CHEMICAL COMPOUND, DIFFERENCES IN HOW/HOW IT WAS PRODUCED SUCH AS DIFFERENT BRAND NAMES)

Therapeutic substitution is the replacement of the originally-prescribed drug with an alternative molecule with assumed equivalent therapeutic effect. The alternative drug may be within the same class or from another class with assumed therapeutic equivalence (I.E. DIFF CHEMICAL COMPOUNDS, BUT THERAPEUTIC OUTCOME SAME)

Question 4

Identify factors affecting the use or not of generic substitution (i.e. using another brand name).

Answer 4

• Cost
• Different bioavailabilities (possibly)
• Patient perception of drug, leading to possible placebo effect

Question 5

How is the possibility for different bioavailabilities of generics regulated in the EU ?

Answer 5

Generics must have a bioavailability of 80-125% compared to the reference product

Question 6

Identify the brand name of the drugs who have been accused of marketing the same drug compound for different needs, as different drugs.

Answer 6

Nurofen

Question 7

Identify the main advantages and disadvantages of oral route.

Answer 7

PROS:

• Cheap
• Convenient (provided patient conscious/can swallow)
• Safe

CONS:

• Possible compliance problems
• Variations in bioavailability of drug

Question 8

Briefly describe the journey of an oral drug through the gut, identify the main factors which means it’s not the full oral drug that reaches the systemic circulation.

Answer 8

• Starts in the mouth.
• Some is destroyed in the gut (from chemical environment, enzymes, microbiota etc)
• Some is not absorbed (i.e. excreted unchanged)
• Some is destroyed by the gut wall (First pass metabolism, through “gut wall enzymes”)
• Some is destroyed by liver (First pass metabolism, drainage of veinous supply from GI organs the drug is passing through, to the liver through portal vein. The liver, through liver enzymes will then change drug into something easier to excrete so lots of drug will be destroyed)

Remainder reaches the systemic circulation unchanged.

Question 9

Identify components of drugs besides the drug compound itself, and the function of each. Will these affect absorption of the drug ?

Answer 9

Excipients- to bulk out the drug
Binding agents- so components of drug stick together
Lubricants
Coatings- protect drug from certain environments, or limit how quickly process occurs is

Yes, these will affect the absorption of the durg

Question 10

How does the size of the drug particles affect absorption ? Explain how pharmaceutical companies may use this to facilitate absorption.

Answer 10

For the drug to be absorbed, it first needs to be completely dissolved into its individual molecules. Anything affecting this dissolution will be affecting the amount of drug that can be absorbed. Such a dissolution is simpler when the drug particles are smaller.
In the case, tablet are solid, then are disintegrated into small drug particles which are then placed in a capsule.

Question 11

Identify any factors which may aid dissolution.

Answer 11

• Size of the particles (smaller = easier to dissolve)
• Time retained in the stomach (if more time, better)
• Anything that increases transit time through GIT can increase time that drug present in body to get through process of dissolution

Question 12

Identify the main routes other than IV which can bypass first pass metabolism, and the main pros and cons of each.

Answer 12

1) Buccal/sublingual mucosa
- Direct absorption into bloodstream (PRO)
- Avoids first pass metabolism (PRO, because veinous supply draining these bypass portal veins)
- Not ideal surface for absorption (smaller area)
- Potential bad taste

2) Rectal mucosa
- Direct to systemic circulation (veinous system avoid portal veins and liver)

Question 13

Identify the main sites in the body the drug goes through (if ingested orally), and the characteristics of each wrt drug absorption.

Answer 13

1) Gastric mucosa
- Can protect drug with enteric coating (want to protect drug, so most dissolution and absorption takes place in small intestine)

2) Small intestine
- Main site of drug absorption
- Large SA, more neutral pH

3) Large intestine/colon
- Poor absorption, long transit times

Question 14

Identify the main ways in which small molecules cross cell membranes. Identify the types of molecules which will use each kind. Which of these are the main ones ?

Answer 14

1) Diffusing directly through lipids (lipophilic drugs)
2) Diffusing through aqueous pores (for diffusion of gases)
3) Transmembrane carrier protein (e.g. solute carriers)
4) Pinocytosis (mostly macromolecules, not drugs)

Diffusion directly through lipids, and transmembrane carrier proteins are the main ones.

Question 15

Identify the main chemical property of drugs which affect their ability to cross membranes.

Answer 15

DRUG IONISATION

When take drug orally, pH difference between GIT and plasma. Lipophilic drugs can only cross plasma membrane if unionised. Majority of drugs will be weak acids or weak bases so pH will influence degree of ionisation

Question 16

Explain how absorption of a weak base happens from the GI to the plasma, and how easily this occurs.

Answer 16

WEAK BASES

• Ionised in acidic pH
• Absorbed in small intestine

In plasma: If follow equation in the plasma, pH of 7.4 and pKa (pH of the solution in which half of the drug is ionised) 6.4 means difference is -1.
inv log of that is 0.1 so that is the ratio between the ionised and unionised forms (more unionised in the plasma).

In small intestine: 10 times more ionised drug (because pH is acidic, 5.4. 6.4 - 5.4 = 1, inv log of 1 is 10 so that is the ratio between ionised and unionised (more ionised in the small intestine).

This would suggest that as we got to the equilibrium, majority of drug is in the small intestine (i.e. incomplete absorption of drug).
The drug in the small intestine being mainly ionised, it would have difficulty getting to the plasma. There would be some drug inside the plasma but because they are unionised, and not getting ionised, majority of it ready to go back in to the small intestine. This would suggests that weak bases have poor absorption profile in small intestine.

BUT
Any drugs across from small intestine into plasma will move away (into other tissues), so in other words no equilibrium, drug always getting washed away
and getting distributed to other tissues.
Since amount of drug in plasma decreases, this will pull more drug from small intestine. Rate will however be limited by degree of ionisation inside small intestine.
So overall, will get very good absorption of weak bases because of big SA, and because of flow away from local environment, but not necessarily fastest of processes.

Question 17

Explain how absorption of a weak acid happens from the GI to the plasma, and how easily this occurs.

Answer 17

WEAK ACIDS

• Unionised in acidic pH
• Absorbed in small intestine

Proton is associated with weak acid and ionisation process is donation of proton (dissociation).

In plasma: high pH, we will have dissociation of proton from weak acid in plasma.
6.4 (pKa)–7.4 (pH)=-1
inv log (-1) = 0.1
[AH]/[A-] = 0.1
i.e. 10 times more of ionised form than unionised form in the plasma

In small intestine: low pH.
6.4–5.4=1
inv log = 10^1 
∴[AH]/[A-] = 10
i.e. 10x more of unionised over ionised form in the small intestine.

Majority of drug in small intestine able to go through plasma membrane, because mainly unionised. Small amount of drug that gets
into plasma gets ionised (so cannot go back into small intestine), and never get into equilibrium because plasma moves weak acid away from local environment.
Overall, better absorption of weak acid in small intestine, in terms of rate and bioavailability.

Question 18

True or False:

Changes in pH of GIT change how well drugs are absorbed. How so ?

Answer 18

True, because they change the relative amounts of ionised and unionised weak acid and weak base drugs, which changes the amount that gets absorbed into the small intestine.

Question 19

Describe the different effects that food can have on drug absorption.

Answer 19

In general food tends to slow the rate of gastric emptying

1) No effect: if the drugs you take are absorbed in stomach and therefore does not matter if longer or shorter in stomach (still very readily and easily absorbed) .

2) Decreased absorption:
- if drug taken is unstable, and finds itself in stomach for long period of time because food has aided retention of contents of stomach, then that can cause degradation, reduce amount of drug that is available to get into systemic circulation, decrease absorption and effectiveness (presystemic metabolism)
- Drug may interact with foods and acids (e.g. oral biphosphonates with calcium rich foods, forming aggregate which cannot be absorbed

3) Delayed absorption:
- Delay in gastric emptying means they do not get into small intestine where more readily absorbed.
- Cmax (max plasma concentration) may be decreased (but exposure to drugs same, and outcome generally the same except delay in alleviation of pain)

4) Increased absorption:
- Increased solubilisation because more time in GI
- Poorly water soluble drugs (e.g. beta blockers) very difficult to dissolute down to drug compound to facilitate absorption, presence of food facilitates that
- Decrease presystemic metabolism (chemical compounds in food inhibit enzymes that would normally degrade that drug (as a result, more bioavailability), e.g. statins and grapefruit juice, latter inhibits enzymes that would normally degrade that drug

OTHER FACTORS OF FOOD WHICH AFFECT DRUG ABSORPTION
1) Type of meal
• Solid v liquid (affects gastric emptying rate)
• Protein and fat content (affects transit time)
• Other dietary factors

2) Is the drug a GI irritant
E.g. NSAID, in which case take it with food to protect GI system

Question 20

Explain the process of Levadopa metabolism and absorption.

Answer 20

if take dopamine orally, to increase dopamine in body (e.g. Parkinson’s disease), gets degraded very rapidly in stomach.
Hence, Levadopa (pro-drug):

-Rapidly taken up from stomach and small intestine into large neutral amino acid transport carriers (LNAA)

(normally, DOPA decarboxylase present in gastric mucosa would convert it into Dopamine, which gets degraded and isn’t taken up in systemic circulation.)

-Another drug, Carbidopa, is given. It will inhibit DOPA decarboxylase in stomach, to allow Levadopa to be taken up into body via LNAA, which gets into systemic circulation and conversion into dopamine occurs in neurons that express DOPA decarboxylase and allow replenishment of NT stores (hence Carbidopa increases bioavailability of Levadopa).

Question 21

Give an example of drug body metabolism is part of the normal process.

Answer 21

Levadopa (pro-drug)

Question 22

Describe the effect of retention of Levadopa in the stomach on its bioavailability.

Answer 22

Retention of Levadopa in the stomach would decrease its bioavailability because DOPA decarboxylase in the gastric mucosa would convert it into Dopamine, which gets degraded and isn’t taken up in systemic circulation

Question 23

Identify drugs whose effects alter drug absorption, explaining how.

Answer 23

Potential for direct or indirect drug interactions affecting absorption too.

Antacids, proton pump inhibitors: Changes in gastric or intestinal pH (affect absorption of weak acids/bases by changing Hendeerson-Hasselback)

Laxatives, anticholinergics: Changes in gastrointestinal motility (changes transit time, changing opportunities for absorption)

Vasodilators: Changes in GI perfusion (increasing GI perfusion and blood flow to specific regions increases absorption by washing drug away from area, which favors movement of drug from small intestine into plasma)

Neomycin: Interference with mucosal function (by causing blunting of vili in small intestine, decreasing SA for absorption, leading to malabsorptive syndroms)

Tetracylcine, Calcium, Magnesium: Chelation (e.g. calcium and biphosphonates, aggregates that don’t get absorbed )

Cholestyramine: Resin binding (can sequester the drug and prevent it getting absorbed)

Charcoal: Adsorption (adherence of drugs to surface of charcoal, preventing their absorption)

Question 24

Describe the effects of intestinal disease on drug absorption.

Answer 24

Absorption rate may be altered due to disease state in the intestine.

Coeliac disease: Gluten-led intolerance leading to autoimmune degradation of small intestine leading to decrease absorptive surface so malabsorption of stuff including drugs

Crohn’s disease: Flare ups of increased motility (decreased absorption) and compromised GI integrity (ulceration etc, creating route to blood supply, which may paradoxically increase absorption) .

Diabetic Gastroparesis: Reduced motility (may suggest increased absorption) BUT “associated including nausea, vomiting, and regurgitation, may delay drug absorption and decrease bioavailability”

Question 25

Identify all the factors that affect oral drug absorption.

Answer 25

DRUG FACTORS:

• Particle size and formation
• Lipid solubility
• Physiochemical (direct drug interactions, dietary factors, ionisation state which partly depends on whether they are weak acid or base + on pH of compartment)

BIOLOGICAL FACTORS:

• Splanchnic blood flow (perfusion of different parts of GI, increased flow increases absorption)
• Surface area (e.g. can be degraded by intestinal disease)
• Compartment pH (can affect ionisation state of drug)
• First pass metabolism (by gut wall or hepatic enzymes)
• GI motility
• Efflux pumps (e.g. P-glycoproteins. They mean drug absorbed in but then hoovered back out into GIT and getting excreted)

Question 26

Identify the main parenteral routes.

Answer 26

Subcutaneous

IM

Question 27

What is the main problem with subcutaneous injections ?

Answer 27

Slow absorption due to blood flow

Question 28

How are different kinds of drug molecules absorbed, in an IM injection ?

Answer 28

1) Lipophilic drugs rapidly absorbed
2) Polar drugs via bulk flow and endothelial cell junctions (they can get into systemic circulation because capillaries inside skeletal muscle not as continuous as in other places,
so opportunity for bulk flow and fluid movement to bring that in to capillaries via fenestrated regions )
3) High MWT or very lipoPHOBIC drugs via lymphatics

Question 29

What factors affect the rate of onset of subcutaneous or intramuscular administration ?

Answer 29

1) Extent of capillary perfusion
2) Drug vehicle (e.g. if put lipophilic drug in oily depot, and inject that, then that will favor staying in oily environment and only slowly leak over time into bloodstream, i.e. slow release)
3) Affected by factors that alter perfusion (e.g. for IM, exercising results in vasodilation which increases absorption)

Question 30

Do we really want to maximise absorption in the systemic circulation for all drugs ? Give examples.

Answer 30

No, for instance inhaled drugs which have an effect on alveolar epithelium and bronchial mucosa (want to have local effects, and avoid systemic side effects).
E.g. salbutamol, ipratropium

Question 31

Identify the kinds of inhaled drugs for which systemic effects are usually wanted/normal.

Answer 31

• Lipid-soluble drugs
– Volatile / gaseous anaesthetics
• Drugs of abuse
• Accidental poisoning

Question 32

Identify ways in which we may modify inhaled drugs to avoid systemic side effects, naming a drug for each method.

Answer 32

– Modify structure, e.g. make them more ionised (ipratropium)
– Particulate size (salbutamol)
– Selectivity for receptors, e.g. beta 2 receptors selectivity (salbutamol)
– Rapid breakdown in circulation (fluticasone)

Question 33

Identify non-parenteral routes of administration, besides oral administration.

Answer 33

Topical
Intranasal
Inhalation
Buccal/Sublingual mucosa
Rectal mucosa

Question 34

Identify the main pros, and cons of intranasal drug administration. Which setting are these increasingly used in ?

Answer 34

PROS:

• Easily accessible
• Rich vascular plexus
• Avoids hepatic first pass metabolism
• Ease, convenience, safety

CONS:
-Limited drugs suitable (high concentrations can be quite toxic to sensitive nasal mucosa)

Increasingly used in pediatrics

Question 35

Identify the parts of the skin that make it a good barrier. What are the implications of the skin being a good barrier, in terms of absorption ?

Answer 35

• Stratified squamous epithelium
• Keratinised layer
• Sebaceous gland secretions

Skin good barrier to stop things getting into systemic circulation , and to limit something to local effect

Question 36

Identify drugs used topically for local effects.

Answer 36

• Corticosteroids for eczema (hydrocortisone)
• Antihistamines for insect bites (mepyramine)
• Local anaesthetics (EMLA)

Question 37

Identify drugs used topically for systemic effects. What properties make them such that they are absorbed, despite the fact that skin is a good barrier ?

Answer 37

• Transdermal patches (HRT, GTN, nicotine)
• Accidental poisoning (AChEsterase insecticides)

These need to be v lipophilic to get absorbed

Question 38

How we know how much drug to give orally ? Topically ?

Answer 38

Doses of oral drug administration depend on weight

Doses of topical drug administration depend on age, which is problematic because SA/V ratio can change for different people of the same age, which can lead to toxicity, with systemic circulation risks). Therefore, SA/V ratio is very important to consider for topical administrations.