03-02-23 - Drug absorption Flashcards
Learning outcomes
- To define what is meant by bioavailability and bioequivalence.
- To explain how the physicochemical properties of a drug, route of administration, drug formulation, gastro-intestinal motility and first-pass metabolism and drug interactions may influence drug absorption.
- To explain the advantages and disadvantages of the oral route.
- To discuss the advantages and disadvantages of specialist routes of administration (e.g. inhalation route, topical route and various common routes of injection for the administration of drugs), when compared to the oral route.
How is bioavailability?
What is the bioavailability of IV injections?
- Bioavailability is the fraction of unchanged drug that reaches the systemic circulation
- IV injection gives 100% bioavailability
What is a generic drug?
How does the bioavailability have to compare between generic drugs and reference product?
What is a generic substitution?
What is a therapeutic substitution?
- A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents
- Generic drugs must have a bioavailability of 80-125% compared to the reference product (EU regulations)
- 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.
- Therapeutic substitution
- 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
What are 3 advantages of the oral route?
What are 2 disadvantages of the oral route?
- 3 advantages of the oral route:
1) Cheap
2) Safe
3) Convenient - 2 disadvantages of the oral route:
1) Patient compliance
2) Variation in bioavailability of drug
What are 4 ways an oral dose of a drug won’t reach systemic circulation?
- 4 ways an oral dose of a drug won’t reach systemic circulation:
1) Destroyed in gut
2) Not absorbed
3) Destroyed by gut wall
4) Destroyed by liver
What are 4 ways oral medication can be given?
What is occurring in each change?
How does time in stomach affection dissolution?
What 4 substances that can change in the formulation of an oral drug?
- 4 ways oral medication can be given:
1) Tablet
2) Capsule
3) Suspension
4) Solution - In each change, the particle size is getting smaller, and the surface area is increasing
- Time in the stomach can aid dissolution (where a solute in gaseous, liquid, or solid phase dissolves in a solvent to form a solution)
- 4 substances that can change in the formulation of an oral drug:
1) Excipients
* An inactive substance that serves as the vehicle or medium for a drug or other active substance.
* Excipients are things like colouring agents, preservatives, and fillers
2) Binding agents
3) Lubricants
4) Coatings
What are 5 locations where oral route medications can be absorbed?
What is the first pass effect?
Where does first pass metabolism take place?
What absorption locations will undergo first pass metabolism?
Which oral drug absorption routes bypass first pass metabolism?
- 5 locations where oral route medications can be absorbed:
1) Buccal / sublingual mucosa
* Direct absorption into blood stream
* Avoids first pass metabolism
* Not ideal surface for absorption
2) Gastric mucosa
* Enteric coating
* Can protect drugs from harsh chemical environet of the stomach that will reduce amount of drug absorbed in the small intestine
3) Small intestine
* Main site of drug absorption – Large surface area, more neutral pH
4) Large intestine / colon
* Poor absorption, long transit times
5) Rectal mucosa
* Direct to systemic circulation
- The first pass effect is a phenomenon of drug metabolism whereby the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the systemic circulation.
- It is the fraction of drug lost during the process of absorption which is generally related to the liver and gut wall (first pass metabolism)
- Drugs absorbed in the gastric mucosa, small intestine, and large intestine/colon will enter blood that is drained through the portal vein towards the liver and undergo first pass metabolism
- Oral drugs absorbed in the Buccal / sublingual mucosa and rectal mucosa will bypass the liver and enter straight into systemic circulation
What are the 4 ways small molecules cross cell membranes?
- 4 ways small molecules cross cell membranes (1 and 3 used for drugs):
1) Diffusing directly through the lipid
* Lipid solubility highly important
2) Diffusing through aqueous pores
* More likely important for diffusion of gases (not for drugs)
3) Transmembrane carrier protein
* e.g. solute carriers
4) Pinocytosis
* Mostly macromolecules, not drugs
What type of compound are most drugs?
When will drugs be absorbed?
When are weak acids and weak bases ionised?
Where are they absorbed?
Why is there varying degrees of absorption along the GI tract?
- Most drugs are weak base or weak acids
- Drugs are absorbed when they are in their unionised form
- Weak bases are ionised in acidic pH and are absorbed in the small intestine
- Weak acids are unionised in acidic pH, but are also absorbed in the small intestine due to the large surface area
What is the pKa value of a weak acid/base?
At what pH value will more of the weak acid/base be ionised?
How does a change of 1 in pH change this?
Describe the ionisation curved for weak acids/bases as pH increase (in picture)
- The pKa value of a weak acid/base is the value at which half of the compound is ionised
- For weak bases, if the pH is above the pKa value, less than 50% of the compound is ionised
- For weak acids, if the pH is above the pKa value, more than 50% of the compound is ionised
- A change of 1 in pH will mean 10 times more of the compound will be ionised/unionised
- Describe the ionisation curved for weak acids/bases as pH increase (in picture)
Henderson-Hasselbach equation for a weak base
Henderson-Hasselbach equation for a weak acid
When are weak acids/based more likely to be absorbed in the GI tract?
- Weak acids are more likely to be absorbed through the wall of the stomach than weak bases would
- This is because more than 50% of the weak acid is unionised in acidic pH, so is more likely to be absorbed
- As we move further down the GI tract, and progress into the small intestines, weak bases are more readily absorbed
How does food affect the rate of gastric emptying?
What are 4 effects food can have on drug absorption?
What are 2 additional considerations to the effect of food on drug absorption?
When might food/liquid be contraindicated with certain drugs?
- In general food tends to slow the rate of gastric emptying
- 4 effects food can have on drug absorption:
1) No effect
2) Decreased absorption
* Intestinal motility
* Interactions with food and acids
* Presystemic metabolism
3) Delayed absorption
* Food slows rate of gastric emptying
* Clinically important?
* Cmax may be ↓ - Cₘₐₓ is the maximum serum concentration that a drug achieves in a specified compartment
4) Increased absorption
* Poorly water-soluble drugs e.g propranolol
* ↑ solubilisation
* ↓ presystemic metabolism
- 2 additional considerations to the effect of food on drug absorption:
1) Type of meal
* Solid v liquid
* Protein and fat content
* Other dietary factors
2) Is the drug a GI irritant?
- Food/liquid can be contraindicated with certain drugs e.g statins and fruit juice
- Fruit juice can inhibit specific enzyme activity, leading to less metabolism of statins, and a greater amount reaching systemic circulation, which could cause toxicity
First pass metabolism: Levodopa uptake.
What is Levodopa used for?
How does it work?
How is it taken up in the GIT?
Where can problems arise in this mechanism?
How can this be avoided?
- First pass metabolism: Levodopa uptake
- Levodopa is a prodrug used in the treatment in Parkinson’s disease
- It is converted into dopamine by DOPA decarboxylase in order to stimulate and replenish neurons
- Levodopa is rapidly taken up from stomach and small intestine by large neutral amino acid transport carrier (LNAA)
- There is DOPA decarboxylase present in the gastric mucosa, which can result in Levodopa being broken down into dopamine in the stomach, which is unstable and degrades instantly
- To avoid this problem, levodopa can be co-administered with carbidopa, which will inhibit DOPA decarboxylase in the gastric mucosa
- Carbidopa is poorly absorbed so wont be able to travel to neurons and inhibit DOPA decarboxylase anywhere else
What are 7 different drugs/types of drugs that alter absorption?
- 7 different drugs/types of drugs that alter absorption:
1) Antacids, proton pump inhibitors
* Changes in gastric or intestinal pH
2) Laxatives, anticholinergics
* Changes in gastrointestinal motility
3) Vasodilators
* Changes in gastrointestinal perfusion
4) Neomycin
* Interference with mucosal function
5) Tetracycline, Calcium, magnesium
* Chelation
6) Cholestyramine
* Resin binding
7) Charcoal
* Adsorption
How can diseased states alter rate of drug absorption?
What are 3 diseases that can alter rate of drug absorption?
- Diseased states can alter rate of absorption by increasing GI motility or compromising GI integrity
- 2 diseases that can alter rate of drug absorption:
1) Crohn’s disease
* Change in absorptive capacity and motility
* Perforations can actually increase absorption in certain regions
2) Coeliac disease
* Affects absorption of diet/drugs
3) Diabetic gastroparesis
* Reduces motility
