L20: Pharmacokinetics Flashcards
What is pharmacokinetics?
Right drug, right condition, right concentration
Maximise therapeutic benefit
Minimise risk of adverse events in patients
What happens to a drug in the body?
Drug in: -Absorption - Distribution Drug out (elimination): - Metabolism - Excretion
How can drugs get into the body?
OI! IT IS SIR! Oral Intravenous Intramuscular Transdermal Intranasal Subcutaneous Sublingual Inhalation Rectal
What is the difference between enteral and parenteral?
Enteral–> delivery into internal environment of body- GI tract (oral, sublingual, rectal)
Parenteral–> delivery via other routes- not the GI tract (intravenous, subcutaneous, intramuscular)
What are the advantages and disadvantages of each of the routes?
Oral–> ad- easy, safest; disad- limited absorption
Intravenous–> ad- immediate effects; disad- unsuitable for oily substances
Intramuscular–> ad- suitable for oily substances; disad- can be painful, affects lab tests
Transdermal–> ad- convenient and painless; disad- some patients allergic
Intranasal–>
Subcutaneous–> ad- suitable for slow release drugs; disad- pain or necrosis if drug is irritating
Sublingual–> ad- bypass destruction by stomach; disad- limited number of drugs
Inhalation–> ad- absorption is rapid; disad- most addictive (enters the brain quicker)
Rectal–> ad- bypass destruction by stomach acid; disad- irritate rectal mucosa, not well accepted route
How is the small intestine adapted for absorption?
6-7m in length
Internal diameter of 2.5cm
Epithelial villi and microvilli increase the surface area further (80-100 fold)
Dynamic environment–> chymes is mixed to increase digestion and contact with the epithelial surface for absorption
Transit time- 3-5 hours
pH is 6-7
What are the four methods of absorption into the vascular system?
Passive diffusion
Facilitated diffusion
Active transport
Pinocytosis
What are the four methods of absorption into the vascular system?
Passive diffusion
Facilitated diffusion
Active transport
Pinocytosis
What is passive diffusion?
Pass down concentration gradient through lipid bilayer
Small intestine highly vascularised
Maintains steep concentration gradient for diffusion
Anything that increases the blood flow (exercise, caffeine) increases the concentration gradient further
Which molecule are capable of passive diffusion?
Lipophilic drugs
Cross the lipid membrane
Small molecular weight <500D and weakly ionic
Which molecules are unable to use passive diffusion?
Ionised molecules
Weakly acidic or basic
Determined by the pKA or pKB of the acid or base (A- and AH or BH+ and B)
What is facilitated diffusion?
Passive process driven by electrochemical concentration gradients
Requires solute carrier transporters
What molecules are capable of facilitated diffusion?
Organic charged molecules up to 500Da
Low lipid solubility with net residual ionic charge
What are the solute carrier transporters (SCTs)?
Transdermal membrane proteins
Split into Organic Anion Transporters (OATs) and Organic Cation Transporters (OCTs)
Expressed throughout all body tissues
In GI, hepatic and renal tissue important for drug absorption and elimination
Give an example of a drug that is carried by an OAT and OCT?
OAT- methotrexate (cancer treatment)
OCT- metformin (diabetes)
OAT and OCT not designed to carry drugs but drugs with similar physicochemical structures ‘sneak past’
How does active transport work?
Uses ATP to move molecules against the concentration gradient
Transport of ionised drugs
What is the difference between primary and secondary active transport?
Primary- ATP used directly to transport molecules across the membrane
Secondary- Uses electrochemical gradient set up by other molecules (Na+ gradient used to co-tranpsort a molecule in e.g.)
What is endocytosis and exocytosis used for?
Transport of large molecules
Endo- Invagination into the surface membrane, taken up into a vesicle
Exo- vesicle fuses with the cell surface releasing its contents
What factors in the stomach and GI tract affect drug absorption?
Drug lipophilicity Surface area Rate of blood flow Intestine motility Presence of food Bacteria and enzymes present pH
What enzymes in the gut are responsible for metabolising endogenous and xenobiotic molecules?
Cytochrome P450s (phase I) and conjugating (phase II) enzymes
Where does most of the drug metabolism occur?
Mostly in the liver but some in the gut by the same enzymes
What is first pass metabolism?
Metabolism of the drugs in the gut and liver before it reaches the systemic circulation
What is a consequence of first pass metabolism?
Reduced amount of drugs reach the systemic circulation
Less drug to exert therapeutic effect
Define bioavailability?
Amount of drug that reaches the systemic circulation
Reflects all the physicochemical and biological
barriers to its absorption and post hepatic systemic distribution
How is the bioavailability calculated?
I = Amount of drug to reach the systemic circulation/ total amount of drug administered
(clinical definition uses drug administered by IV route)
What is oral bioavailability?
F= Total amount of drug administered by the oral route/ total amount of drug administered by the IV route
Why is the oral bioavailability an important calculation?
Determine optimal route of administration
Help determine amount of drug in oral formulation
What is meant by distribution?
How the drug reaches and interacts with the target site
Dependent on the physiocochemical properties of the drug
What are the different methods of distribution through the body?
Bulk flow- rapid distribution over large distances - arteries to capillaries
Diffusion- smaller distances, from capillaries into interstitial fluid and tissues
What determines the rate of delivery of a drug?
Density of capillary supply - reaches vascularised organs first
Diffusion affected by microleakiness of the capillaries- e.g fenestrated capillaries, sinusiods (slit junctions or large intracellular gaps)
What factors affect drug distribution throughout the body?
Lipophilicity/ hydrophilicity
Degree of binding to plasma proteins
Degree of binding to tissue proteins
Mass or volume of tissue and density of binding sites within that tissue
How does lipophilocity/ hydrophilicity affect drug distribution?
> > lipophilicity pass through membranes easier
If the drug has net negative charge, can pass out through endothelial fenestration but uptake into tissue is dependent on local pH
How does binding to plasma proteins or tissue proteins affect it?
Lots of proteins in the serum- albumin main one, binding is relatively weak electrical polar bonding but forces are sufficient for sites en mass to act as a large reservoir
Tissue proteins such as muscle affects the amount of free drug available (removes it from the plasma)
How does mass or volume of tissue and density of binding sites within that tissue?
Varies from individual to individual
More tissue more binding sites etc…
In the compartments model, where does each drug pass through?
Plasma → interstitial fluid → intracellular fluid
What is the volume of distribution (Vd)?
Volume into which the drug appears to be distributed when only the sample concentration is considered- plasma concentration is used as it can be measured
Describes the movement from plasma → interstitial fluid → intracellular fluid
How is the Vd calculated?
Total amount of drug in the body plasma (dose/mass) / concentration of drug at t=0 (calculated from taking a sample of blood)
What do the Vd results tell you?
Large volume of distribution means that more of the drug has moved into the interstitial/intracellular fluid compartment (smaller concentration of drug- bottom number)
Smaller volume of distribution means less penetration on interstitial/intracellular fluid compartments
How is the apparent Vd calculated?
Pretend the drug is equally distributed throughout the body as soon as it is given
Extrapolate back along the log drug concentration curve until it reaches the y axis which is t=0
What is the apparent Vd?
After the grouping of body compartments
Why does volume distribution have to be considered?
Vd affected by protein binding throughout different body compartments Other drug (polypharamacy) can also affect binding sites
