Pharmacokinetics & dynamics Flashcards
What do drugs from different routes all go to
Plasma
From where do we measure drug concentrations
plasma
Label the graph
What absorption routes follow zero order and which follow first order
IV infusion = zero order kinetics
IM/SC/oral = tend to follow first order kinetics
First order: the greater the concentration the greater the rate
Define bioavailability (F)
Measure of extent of absorption from administration site to measurement site (plasma)
fraction/percentage of administered dose that reaches plasma
Incorporates absorption and first-pass metabolism
What is the distribution phase of a drug
process of drug moving from bloodstream into tissues and fluids of the body
What kind of drugs can move across membranes?
Higher lipophilicity = greater membrane permeability
Only uncharged drugs can pass through membrane core
Certain ionic compounds may go through as ion pair or through ion channel
What role do transport mechanisms play in drug distribution?
Drugs may use active transport or carrier-mediated transport, which allows movement against concentration gradients but may saturate at high drug concentrations.
What factors influence drug distribution across membranes?
Lipophilicity
degree of ionization (low can cross)
molecular weight (<1000)
affinity for transporters.
Define volume of distribution (Vd)
volume into which drug appears to be distributed with
concentration equal to that in plasma
Vd is reversible process, however, together with drug clearance (irreversible) influences rate of drug elimination
What influences Vd?
magnitude of Vd for a drug is influenced by its reversible affinity for tissue proteins versus plasma protein
high affinity = high distribution
What does Vd indicate about a drug’s distribution?
It shows whether a drug is mainly confined to plasma, extracellular fluid, or distributed widely into tissues.
What is the typical Vd for drugs that are water-soluble and remain in extracellular fluid?
Between 0.1–0.3 L/kg, such as NSAIDs
What does a high Vd (e.g., 2 L/kg or more) indicate?
drug accumulates in tissues, such as fat or other compartments, as seen with general anesthetics like fentanyl.
Name 2 barriers to distribution
Blood-brain barrier
Placenta
How does the blood-brain barrier affect drug distribution?
It restricts most drug entry due to tight junctions, transporters, and efflux pumps
However, if diseased barrier can become leaky
How do drugs cross the placenta?
Most drugs that can be absorbed orally can cross the placenta, often through passive diffusion.
What is ion trapping in the context of the placenta?
It occurs when basic drugs accumulate on the fetal side due to differences in pH
What is drug elimination rate
amount of parent drug eliminated from body per unit time
Elimination rate is defined with respect to irreversible removal of parent drug and does not include metabolites
Units: Mass or Moles per time
What are the primary routes of drug elimination?
Kidneys, hepatobiliary system, and lungs (for volatile compounds).
What are the secondary routes of drug elimination?
milk, sweat
What are the 2 elimination processes that drugs can go through
Describe drug metabolism
Liver protects the body from drugs/xenobiotics
Lipophilic drugs will be transformed to become hydrophilic (polar), often inactive, and then be excreted.
The drug transformation may be a 2-phase reaction (but the phase I may be sufficient to inactive and excrete the drug)
What are the two phases of drug metabolism?
Phase I (catabolic reactions: oxidation, reduction, hydrolysis) and Phase II (anabolic reactions: conjugation).
What happens during Phase I metabolism?
The drug is chemically modified, often making it more reactive or preparing it for conjugation in Phase II.
What is the role of CYP enzymes in drug metabolism?
They catalyze Phase I reactions, including oxidation, reduction, and hydrolysis, to modify drugs for further metabolism or excretion.
What is the main conjugation reaction in Phase II metabolism?
Glucuronidation, where drugs are conjugated with glucuronic acid to form water-soluble metabolites.
What is the outcome of drug metabolism?
The formation of water-soluble metabolites, which are usually inactive and ready for excretion.
What is the role of CYP450 in drug metabolism
phase 1 oxidation
Why do different animals react differently to the same drug?
Different animals have varying CYP enzyme profiles, leading to differences in drug metabolism.
What does the term “non-specific” mean regarding CYP enzymes?
CYP enzymes can act on multiple substrates, not limited to a single specific compound.
Which enzyme family is primarily responsible for glucuronidation?
Uridine Diphosphate Glucuronyl Transferases (UGTs).
Why are cats prone to toxicity from drugs like paracetamol?
Cats have a deficiency in UGT enzymes, limiting their ability to perform glucuronidation.
Where are glucuronide conjugates excreted?
In bile and urine
What is the significance of glucuronidation in drug metabolism?
It transforms lipophilic drugs into hydrophilic forms, facilitating their elimination from the body.
How are polar vs non-polar drugs excreted?
What are the main processes of renal drug excretion?
Glomerular filtration (filters free drug), tubular secretion (actively transports drugs into tubules), and tubular reabsorption (lipophilic drugs may re-enter the bloodstream).
How does urine pH influence drug excretion?
Alkaline urine enhances the excretion of weak acids, while acidic urine enhances the excretion of weak bases.
What factors affect renal drug excretion?
Glomerular filtration rate (GFR), plasma protein binding, drug polarity, urine pH, and affinity for transport proteins.
What is drug clearance
The volume of blood/plasma cleared of a drug per unit time, expressed as L/h/kg
What is the half-life of a drug?
The time it takes for the plasma concentration of a drug to reduce by half.
What factors affect half life?
Larger clearance = shorter half life
Higher volume of distribution = longer half life
What is polypharmacy?
The concurrent use of multiple drugs, increasing the risk of drug interactions
What are the three main types of drug-drug interactions?
What is summation?
What is potentiation?
What is Synergism?
What are pharmaceutical drug interactions?
Interactions that occur before drug administration, often due to physical or chemical incompatibilities
What is an example of physical incompatibility in pharmaceutical interactions?
Binding of drugs to plastic containers or infusion sets (e.g., diazepam binding to plastic)
Insolubility: Certain drugs precipitate in solutions, such as amphotericin B in electrolyte solutions
What are examples of chemical incompatibility in pharmaceutical interactions
Stability of drugs is often pH dependent e.g. penicillin G is inactivated by alkaline sulphonamide
Oxidation/reduction reactions e.g. tetracyclines are oxidised by
riboflavin
Complex formation eg chelation of drugs
Inactivated by certain vehicles eg Fluoroquinolones can be inactivated in calcium-containing solutions
What are pharmacokinetic drug interactions?
Interactions where one drug alters the absorption, distribution, metabolism, or excretion of another drug
How can absorption be affected in pharmacokinetic interactions?
Altered gastric pH (e.g., antacids reducing the absorption of acidic drugs).
Chelation in the stomach (e.g., calcium binding to tetracyclines).
Altered gastric emptying (increasing or decreasing absorption).
Interference with intestinal efflux proteins (e.g., P-glycoprotein inhibition).
How do pharmacokinetic interactions affect drug distribution?
Competition for plasma protein binding sites (though clinically less significant).
Altered blood flow to organs (e.g., reduced organ perfusion affects distribution and clearance).
Interactions with tissue transport proteins.
What are the two main ways metabolism is affected in pharmacokinetic interactions?
Enzyme induction: Increases drug metabolism, reducing plasma drug levels.
Examples: Barbiturates, carbamazepine.
Enzyme inhibition: Decreases drug metabolism, increasing plasma drug levels.
Examples: Fluoroquinolones, azole antifungals, grapefruit juice.
How can excretion be altered in pharmacokinetic interactions?
Urinary pH will alter clearance of renally excreted drugs i.e. more alkaline will increase excretion of weak acids
What are additive effects in pharmacodynamic interactions?
When the combined effect of two drugs equals the sum of their individual effects
Can be beneficial or detrimental
Enables reduced doses to be administered: e.g.
- Barbiturates & benzodiazepines for sedation
- Opioids and NSAIDs for analgesia
Can lead to increased toxicity e.g.
- NSAIDs & steroid: increased risk of GI ulceration
- NSAIDs & aminoglycosides: increased risk of nephrotoxicity
What is synergism in pharmacodynamic interactions?
When the combined effect of two drugs is greater than the sum of their individual effects.
Example:
- Sulphonamide and trimethoprim (enhanced antibacterial effects).
- Aminoglycosides and furosemide (toxicity).
What is negation in pharmacodynamic interactions?
When one drug opposes the action of another, reducing its effect.
Examples:
- Atipamezole reversing medetomidine.
- Naloxone reversing opioids
Define adverse events
Unintended or noxious response to a drug that occurs within a reasonable time frame following administration
What are some “use-patterns” associated with increased ADE
Use of human-label drugs (haven’t undergone same testing)
Drugs with low therapeutic indices (non-selective)
Inappropriate (trivial) use
Lack of therapeutic goals
Multiple drugs
Young, old, altered PK
What are the different types of adverse events?
