Pharmacokinetics/dynamics Flashcards
Pharmacokinetics:
How a drug molecule moves through your body from administration to elimination (really not related to how a drug helps you)
Pharmacodynamics:
How a drug molecule affects its target to produce the desired physiological effect.
4 subcategories of pharmacokinetics:
Absorption Distribution Metabolism Clearance
Key points of Absorption:
- Drug must cross epithelial cell layers to enter body 2. Drug molecules cross cellular plasma membranes by passive diffusion, facilitated diffusion, or active transport based on their physical properties 3. Drug molecules must be neutrally charged to cross PM by passive diffusion 4. The pH of the environment can affect the charge state of a drug and alter its absorption 5. A drug’s bioavailability is related to how efficiently it is absorbed 6. Most drugs must reach the blood in order to be distributed effectively (except topicals)
Absorption is affected by:
- Surface area (e.g. much larger SA in small intestine than mouth) 2. Drug transit time (e.g. drug rapidly moves through esophagus but moves slow through small intestine) 3. pH of the lumen (different drugs are absorbed in different locations depending on pH - e.g. stomach has 1.5-3.5, small intestine has 6-7.4)
The __________ is the primary site of drug absorption?
Small intestine (but remember, it does depend on the drug!)
Once a drug is absorbed, it has to pass through __ layers of lipid bilayer, which are _________.
4 hydrophobic
What are the consequences of a drug that relies on passive diffusion vs. facilitated diffusion vs. active transport to pass through epithelial cell layers?
Passive diffusion allows the drug to keep moving through. No Vmax. Facilitated and active require transport proteins, which can become saturated and limit movement. At this point, passage plateaus and the Vmax is reached.
The ______ ______ of a drug affects its ability to diffuse across cell membranes
charge state (hydrophobic passes MUCH more readily)
At what pH are weak acids more hydrophobic?
Low pH (high H)
At what pH are weak bases more hydrophobic?
High pH (low H)
weak ______ are absorbed better in small intestine, while weak ____ are absorbed better in the stomach
weak bases - small intestine weak acids - stomach
What types of drugs have a bioavailability of 100%
IV drugs only
Define bioavailability:
the fraction of a drug dose that reaches the systemic circulation.
Illustrate the differences in the bioavailability curves for IV drugs vs. non-IV drug.
IV drugs have sharp, quick spike in plasma concentration. The drug will decrease as it is distributed throughout the body. Other drugs take longer to reach their peak because the absorption in e.g. the gut will take longer, and the peak itself is lower because not all of the drug will be absorbed.
How is bioavailability calculated?
By measuring the area under the curve. Bioavailability is always compared relative to the bioavailability of the IV route (100%) **it is important to specify the route of administration, because this impacts the bioavailability
Oral drugs are subject to the “____ _____ _____” in the liver due to _____ ______
“first pass effect” portal circulation
First Pass Effect:
Drugs are picked up via the mesenteric artery in the small intestine and sent to the liver before they are released into the general circulation. Important because bioavailability of drugs is measured after the pass through the liver, and takes into account the fraction that is absorbed into the gut and then survives metabolism and clearance through the liver.
The bioavailability of oral drugs is measured _____ the First-pass effect
after
Some oral drugs are degraded by intestinal bacteria. How does this affect absorption and bioavailability?
Decreases absorption and bioavailability Gut bacteria can degrade drugs that are taken orally by chemically breaking them down and rendering them in-absorbable, inert, etc.
Key points of distribution phase:
- Most drugs must reach the blood to be distributed effectively 2. oral drugs are subject to first-pass effect which reduces bioavailability 3. once in the blood, drugs distribute to various tissues and body water compartments according to their physical properties 4. Drug binding to serum proteins affects distribution and clearance 5. Vd of a drug describes the distribution of a drug across the 3 body water compartments, and is crucial when calculating the rate of drug clearance.
What is the average total body water breakdown?
Average body is 60% by weight water (avg. 75kg person) 4% plasma (3 L) 16% interstitial (12 L) 40% intracellular (30 L)
What impacts the movement of a drug throughout the body?
Drugs move from plasma to interstitial to intracellular -Protein binding impacts plasma to intracellular -charge state impacts entry/exit to/from interstitial -transporters impact entry/exit to/from interstitial -hydrophobicity, pH trapping, and binding to tissue targets impacts entry/exit to/from intracellular
A Vd of _____ means a drug distributes evenly across all body compartments
0.6 L/kg e.g. ethanol
A Vd LOWER than 0.6 L/kg means:
The drug is preferably kept retained in the plasma
A Vd HIGHER than 0.6 L/kg means:
The drug is actively drawn out of the plasma and into other tissues
Aside from its conceptual importance, Vd is necessary to calculate _____ and _____
Drug half-life Loading dose
Key points of Metabolism phase:
- the cytochrome p450 liver enzymes are largely responsible for the chemical degradation/modification of drugs via phase 1 and 2 reactions 2. Both types of reactions reduce drug efficacy, and increase the polarity of drug molecules, facilitating renal clearance 3. Drugs may be metabolized via first-order or zero-order kinetics, depending on the saturation of the enzymes involved 4. Many drug-drug interactions result from effects on the CYP450 systems
Most drug metabolism occurs in the _____.
Liver (although can also occur in kidneys, GI tract, lungs)
Drugs are metabolized in order to _______ them, and to facilitate their ______ via urine or feces
Drugs are metabolized in order to INACTIVATE them, and to facilitate their ELIMINATION via urine or feces
Phase 1 Metabolization:
“Functionalization Phase” Most commonly oxidizes the molecule (which makes it easier to conjugate in phase 2)
Phase 2 Metabolization:
“Conjugation Phase” Add on a group - most common is glucuronidation
What is the purpose of Phase 1/2 Metabolization:
These reactions are meant to increase the chemical polarity of the molecule and increase the rate of clearance via kidneys and GI tract
Phase 1 oxidation is most commonly catalyzed by:
Cytochrome p450 (15 families)
Which CYP families are responsible for the Phase 1 metabolism of most drugs in clinical use?
CYP families 1, 2, and 3
