drug absorption Flashcards
Four basic factors determine drug pharmacokinetics:
Absorption
Distribution
Metabolism
Elimination
To have biological action most drugs must
enter the blood stream and be distributed to a site of action
Absorption =
process of movement of unchanged drug from the site of administration to the systemic circulation.
There is always a correlation between plasma concentration of a drug and the therapeutic response.
Oral Absorption considerations
The time to peak concentration (Tmax)
The peak concentration (Cmax)
The area under the drug concentration-time curve (AUC)
Amount of drug which enters the systemic circulation
Speed at which this happens
The more rapid the rate of absorption,
the earlier the drug concentration peak.
Tmax
Increasing dose does not affect
the time at which peak concentration is reached but does increase the peak concentration.
Cmax
The area under the drug concentration-time curve represents
the amount of drug which reaches the systemic circulation: bioavailability.
AUC
Therapeutic Range =
A drug is active over a range of concentrations.
Below this there will be insufficient or no pharmacological action.
Above this toxicity occurs
therapeutic index
measure of the range at which a drug is safe and active.
A drug given intravenously has bioavailability of
100%
Factors Affecting Bioavailability (Oral Absorption)
Formulation
- Slow release preparations
Ability of drug to pass physiological barriers
- Particle size
- Lipid solubility
- pH and ionisation
Gastrointestinal effects
- Gut motility
- Food
- Illness
First pass metabolismPhysiological Barriers
Passive diffusion
Filtration
Bulk flow
Active transport
Facilitated diffusion
Ion-pair transport
Endocytosis
Diffusion - Ionisation
- Most drugs do not completely ionise in water.
- As most drugs are weak acids or bases the degree of ionisation depends on the pH of the environment.
- Both ionised and un-ionised forms will be present.
- The ionised drug does not cross the membrane.
- The un-ionised form should distribute across the membrane until equilibrium is reached – an equal concentration at each side.
- An acidic drug will be more concentrated in the compartment with high pH (‘ion trapping’)
- The relationship between the local pH and the degree of ionisation is described by Henderson-Hasselbalch equation.
- The result is that small changes in pH may significantly influence the ionisation of a drug and so the rate of absorption or diffusion.
- Proton pump inhibitors and antacids
aspirin is a weak acid, so should be absorbed more easily from the
stomach.
However there may be more important factors such as available gut surface area, so in fact aspirin is more absorbed from the small intestine. Even though it is more ionised and less lipid soluble
Diffusion – Lipid Solubility
- To pass across a lipid layer a drug must be in solution and be lipid soluble.
- The ability of a drug to diffuse across a lipid barrier is expressed as a lipid-water partition coefficient.
- This is the ratio of the amount of drug which dissolves in the lipid and water phase when they are in contact.
- A drug that is highly lipid soluble will rapidly diffuse across a cell membrane.
- Reach the brain, ovaries, testes and liver
- A drug that is not lipid soluble may not be absorbed at all, for example gentamicin
lipid-water partition coefficient =
The ability of a drug to diffuse across a lipid barrier
what type of diffusion is most common
passive is more common
active is a bit unusual
Active Absorption
Relatively unusual. Occurs against concentration gradient. Requires carrier and energy. Specific Saturable. Iron ,K , Na , Ca eg- Uptake of levodopa by brain.
To undergo active transport drugs must
resemble naturally occurring compounds.
The drug is reversibly bound to a carrier system.
Facilitataed Diffusion
Require carriers Saturable Structure specific No energy required Mixed order kinetics eg- monosaccharides, amino acids, vitamins
Passive Diffusion
Non selective Not saturable Requires no energy No carrier is needed Depends on lipid solubility and degree of ionsation
Filtration / Bulk Flow/ Pore Transport involves
Generally water-soluble drugs e.g. urea, water & sugars, renal excretion, removal of drug from CSF & entry of drug into the liver
Filtration normally occurs through
channels in the cell membrane.
Filtration / Bulk Flow/ Pore Transport:
The driving force for the passage of the drugs is the
hydrostatic or the osmotic pressure difference across the membrane.
Gastrointestinal Factors and Motility
Speed of gastric absorption will affect speed at which drug reaches site of absorption (most drugs are absorbed in small intestine).
Can be affected by other drugs, food/drink and illnesses (esp pain).
Gastrointestinal Factors and Food
Can enhance or impair rate of absorption.
Gastrointestinal Factors and Illness
Malabsorption (eg Coeliac disease) can increase or decrease rate of absorption
Migraine reduces rate of stomach emptying and therefore rate of absorption of analgesic drugs.
First Pass Metabolism
Metabolism of drug prior to reaching systemic circulation can happen in
Gut lumen (acid, enzymes) Gut wall (metabolic enzymes) Liver (hepatic enzymes) These factors can be changed by drugs and disease
oral cannot be used for
insulin
Subcutaneous / Intra-muscular
Can change the rate of absorption from these sites with different physical properties of formulation.
Depends on blood flow to site.
Needs small volume.
Avoids first pass metabolism.
Some drugs not well absorbed from this route (water soluble better)
Sublingual, Buccal
Sublingual absorption from the buccal mucosa bypasses first pass metabolism which will inactivate the drug.
Drugs given this way enter the circulation directly
i.e. GTN for angina
Rectal
Drugs given via the rectum bypass first pass metabolism.
Absorption tends to be slow.
The rectum is often used for drugs which cause irritation of the stomach.
Inhalation / Nasal
Depends on type of delivery system, particle size, patient technique. Better for volatile agents. Can be metabolism in lungs. Relatively rapid action. About 5-10% absorbed.
Usually used for topical effect or to avoid problems of oral absorption (eg nausea).
Transdermal
Avoids first pass metabolism.
Can provide controlled release.
Few substances well absorbed.
Need to be non-irritant.
Considerations for mode of administration
Purpose and site of drug action
- Local absorption
- Avoid first pass metabolism
Disease effects
Patients ability to take medicine
Speed of action
Reliability of absorptionDrugs generally need to reach
systemic circulation to reach target tissues.
Different methods of absorption in order to ensure this occurs.
Chemical properties determine
absorption at different sites – particularly lipid solubility and ionisation.
A number of physiological changes, disease states, drugs and food/drink can influence this.
