L10 - Absorption and distribution of drugs Flashcards
Describe the fate of an orally transmitted drug
- Not dissolved - total oral dose
- Dissolved in GIT
- Broken down in stomach (acid) or intestine
- Not absorbed
- Secreted into bile - Absorbed
- In liver
- Secreted into bile
- Metabolised = first pass metabolism - General circulation
- Bound to plasma proteins (to tissues) - In tissues
- Metabolised/ excreted
- Tissue bound (to site of action) - At site of action
Where can metabolism occur?
- Liver
- First pass metabolism - Kidney
- Skin, lungs
- Microbiome
- Basically anywhere in body
- Conjugation to small soluble molcs (e.g. sulfation pathways)
What happens in phase 1 of biotransformation?
- Oxidation via cytochrome P450 enzymes
- Intro of hydroxyl groups
- Compounds get more hydrophilic
- Occurs simultaneously as phase 2
What happens in phase 2 of biotransformation?
- Conjugation reactions
- Charged groups are conjugated (linked) to compounds
- Compounds get even more hydrophilic
Groups to be linked: - Sulfate
- Glucuronidate
- Occurs simultaneously as phase 1
What is the definition of absorption?
Movement of a drug from its site of administration into the plasma
- Tends to involve passage through layers of cells (epithelia)
What is the definition of distribution?
Reversible transfer of a drug from one location to another within the body
- Tends to involve passage through layers of cells (epithelia)
What does lipophilicity strongly depend on?
Whether a compound can pass through membranes
What is the relationship between ionised and unionised forms of a drug?
Many drugs exist in equilibrium between ionised and unionised forms
- Only the unionised form is sufficiently lipid-soluble to diffuse through membranes
Where will drugs tend to accumulate?
Drugs will tend to accumulate in areas where ionisation is favoured
Many drugs are weak acids or weak bases, what will this mean?
- Their pKa values are in the physiological pH range
- The degree of ionisation depends on local pH
What does absorption depend on?
- Route of administration
- Blood flow at site of administration
- Dose of drug
- Active v passive diffusion through a membrane
- Drug solubility
- Bioavailability
What is bioavailability?
The fraction of the total dose administered that reaches the plasma
What are the different routes of drug administration?
- Enteral routes
- Oral
- Rectal - Parenteral routes
- Subcutaneous
- Intra-muscular
- Intra-venous
- Intra-arterial
- Intra-thecal
- Intra-peritoneal - Percutaneous (by way of skin)
- Inhalation
- Sublingual
- Topical/ transdermal
- Through mucous membranes (e.g. intranasal)
What are the different pharmaceutical interventions that can influence absorption?
- Particle size
- Dry-powder inhaler
- Enteric coated tablets (slow release)
- Slow/ delayed release preparations
What factors can affect transdermal absorption?
- Lipid solubility
- Formulation
- Skin thickness
- Area
- Age
- Damage - Hydration
- Occlusive dressings - Blood flow
What does distribution depend on?
- Ability of the drug to pass through …?
- Blood brain barrier
- Placenta - Tissue binding
- Blood flow
4.
What is the definition of apparent volume of distribution (AVD)
The notional volume of fluid required to dilute the absorbed dose to the concentration found in plasma
What is the formula of AVD?
AVD (vol) = dose (unit of mass) / [plasma] (mass/vol)
What does an AVD=6 litres say about a drug?
Drug is heavily plasma-protein bound
What does an AVD > 70 litres say about a drug?
Drug is heavily tissue bound
What are the different ways that a drug can be eliminated?
- Urine
- Faeces
- Milk, sweat
- Expired air
What is ion trapping?
The build up of a higher conc of a chemical across a cell membrane due to the pKa value of the chemical and difference of pH across the cell membrane
- Does not require any enzyme of energy
How is ion trapping similar to osmosis?
They both involve the semi-permeable nature of the cell membrane
Where will weak acids tend to be well absorbed?
Weak acids tend to be well absorbed from acid environments and accumulate in basic environments
Where will weak bases tend to be well absorbed?
Weak bases will tend to be well absorbed from basic (alkaline) environments and accumulate in acidic environments
Why are basic (alkaline) drugs secreted into the stomach
Due to ion trapping
- pH is acidic in the stomach, therefore alkaline drugs are secreted into the stomach
Where can acidic drugs excreted?
Acidic drugs are excreted in urine when it is alkaline
What factors affect the abs of drugs from the GIT?
- Dispersal/ solubility of drug in gut contents
- Formulation - Stability of the drug
- Acid/ alkali and digestive enzymes - Lipid solubility of the drug
- Time available for abs
- Transit time
- Diarrhoea and vomiting - Conc of drug
- Blood flow
- Interaction with food
- Effect of drug on GIT (irritant etc)
- Effect of meals
- First pass metabolism?
