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
_____ transferases are responsible for the Phase II metabolism of clinically-relevant drugs
VARIOUS transferases are responsible for the Phase II metabolism of clinically-relevant drugs.
What order are drugs metabolized in?
Drugs can undergo phase I only, phase II only, or phase I followed by phase II. NOT reversed. BUT many drugs actually undergo many different pathways, meaning that a different fraction of a dose might be metabolized a certain way. (Metabolites themselves can be toxic)
How is Clopidogrel (Plavix) metabolized?
This drug is taken in its INACTIVE form, and relies on phase I reactions to convert it to its ACTIVE form.
The rate of drug metabolism depends on how much drug there is relative to the _________
The rate of drug metabolism depends on how much drug there is relative to the METABOLIZING ENZYME. (The rate at which drugs are metabolized and eliminated will affect how the drug is used therapeutically)
First order kinetics
Enzymes in excess Clearance rate (CR) dependent on drug concentration Constant % eliminated per hour Half life is constant (Basically, exponential decay - more intuitive)
Zero order kinetics
Drug in excess Clearance rate (CR) independent of drug concentration Constant mg/hour eliminated Half life not constant
The rate of drug metabolism depends on how much ___________ and _______ there are
The rate of drug metabolism depends on how much DRUG and METABOLIZING ENZYME there are
What is a good example of a zero-order kinetic drug?
Alcohol - this is one of the few drugs that can be consumed in high enough quantities to be eliminated via zero-order kinetics
Key points for Clearance phase:
- Some drugs modified in the liver and cleared via the GI tract may be subject to “enterohepatic circulation” 2. Antibiotics may alter the EHC process, affecting a drug’s pharmacokinetic profile
Enterohepatic circulation:
Sometimes gut bacteria can reverse the phase I/II modifications and revert the drug to its original form, allowing drug reabsorption and essentially providing the body a second dose. **Key implication: if a patient is given antibiotics, this can interrupt gut flora and thus impact the enterohepatic circulation of another drug
The biological ______ of some drugs is significantly increased by enterohepatic circulation
The biological HALF-LIFE of some drugs is significantly increased by enterohepatic circulation
Key points about drug-drug interactions and individualized treatment:
- One drug can alter another’s therapeutic and toxic effects by affecting its absorption, distribution, metabolism, or clearance 2. Drug doses should generally be reduced for elderly patients due to reduced Vd, hepatic function, and renal function 3. “Beers Criteria for Potentially Inappropriate Medications Use in Older Adults” 4. Genetic polymorphisms affecting the activities of various proteins involved in PK account for a large part of the variability in drug response among individuals
Absorption Interaction: Omeprazole and Cefpodoxime
Omeprazole is a proton pump inhibitor used to reduce stomach acid. Cefpodoxime is an antibiotic that is made more absorbable by stomach acid Omeprazole causes increase in stomach pH, making Cefpodoxime less absorbable in the stomach
Absorption interaction: Digoxin and antibiotics
Digoxin co-administered with antibiotics will result in increased absorption, resulting in drug overdose/toxicity
Distribution interaction: NSAIDs and Warfarin
Warfarin is almost completely bound to plasma proteins, specifically albumin. This is also the site where NSAIDs bind. NSAIDs can outcompete warfarin and result in more free-floating warfarin which increases blood thinning and puts patient at a greater risk for bleeding
Metabolism interaction: Omeprazole and Clopidogrel
Omeprazole inhibits CYP2C19. Clopidogrel (anti-coagulant) is activated by CYP2C19. Taking the two together results in reduced efficacy of Clopidogrel and increased clotting risk
Clearance interaction: Verapamil and Digoxin
P-glycoprotein transporter in kidney normally pumps Digoxin into urine for elimination. P-gp is inhibited by Verapamil, resulting in too much digoxin in the blood/toxicity
The pharmacokinetics of drugs are affected by patient-specific factors, especially:
Age Body composition Health status (e.g. liver disease, kidney disease) Genetic profile (polymorphisms in PK proteins)
What physiological changes are associated with age that impact pharmacokinetics?
Absorption - reduced SI surface area, increased gastric pH (don’t see increase dosing however) Distribution - Reduced body water content, increased body fat content (decrease dosing) Metabolism - reduced liver function (decrease dosing) Clearance - reduced renal function (decrease dosing)
Polymorphisms and pharmacokinetics:
Proteins are involved at all stages - transport proteins in absorption, serum proteins in distribution, enzymes in metabolism, and transport proteins in clearance. PROTEINS ARE SUBJECT TO MUTATION, and individual polymorphisms can impact function at all stages.
What is the equation that governs the dose-response curve for the relationship between drug concentration and receptor occupancy?
Y = [D] / (Kd + [D])
Define drug potency:
Potency is defined by how little or how much drug is required to achieve the effect. Is independent of efficacy.
On the curve, the potency is the change in left to right.
Define drug efficacy:
Efficacy is a description of how much effect the drug can potentially produce. Can have the same total efficacy even if it takes different drugs different concentrations to achieve the same effect. Is independent of potency.
On the curve, is basically the Vmax
Why do receptor occupancy and therapeutic effect not necessarily correlate?
Signal amplification.
E.g. one molecule can activate a receptor, which can initiate a signaling cascade that activates a number of different molecules at each step with a signal amplification at each stage.
Agonists:
Mimic the effects of endogenous molecules
Antagonists
Block the effects of the endogenous molecules
Competitive antagonist
Binds reversibly to the receptor at the same site that the normal ligand does. The antagonist and the ligand compete with each other for binding.
Non-competitive antagonist
Can be either reversible or irreversible. In both cases, they do not directly compete with the agonist for receptor binding.
- Can bind at a different site reversibly, changing the conformation of the receptor
- Can bind irreversibly and never come off the receptor, and so no matter what the agonist does, it can’t compete with the bonund agonist.
Full agonist:
Elicits the maximal response from its receptor.
Can either be an endogenous molecule or a drug.
Partial agonist:
Elicits a sub-maximal response from its receptor
Some drugs are partial agonists.
Neutral antagonist:
Reduces the effect of an agonist, but has no effect itself.
Many drugs are neutral antagonists.
Inverse Agonist:
Different from antagonists because they are not competing with the endogenous agonist.
What is the distribution of an average 75 kg person’s body water?
An average person is 60% water.
3L in plasma
12L in interstitial
30L in intracellular
What is the Vd of a drug that readily crosses all cell membranes?
45L or 0.6
What do acidic drugs bind to in the plasma?
Albumin
What do basic drugs bind to in the serum?
alpha-1 -acid glycoprotein
What do hydrophobic drugs bind to in the serum?
Lipoproteins
What do steroid hormones bind to in the serum?
Globulins
The fraction of a drug that is associated with plasma proteins is ________ of that particular drug
The fraction of a drug that is associated with plasma proteins is CHARACTERISTIC of that particular drug.
Regardless of whether your adminster 10mg or 20mg of warfarin, 95% will always be protein-bound.
How does water content vary by tissue?
Brain and muscle = 0.75 L/kg
Adipose tissue = 0.1 L/kg
Vd formula:
Vd = Q/Cp
(volume of distribution = dose / plasma concentration)
The less drug that remains in the plasma, the _______ the Vd will be
The less drug that remains in the plasma, the HIGHER the Vd will be
Highly lipophilic drugs typically have a _____ Vd
Highly lipophilic drugs typically have a HIGH Vd
pH trapping:
pH trapping causes weak bases to move down the pH gradient that exists between the slightly basic interstitial and plasma compartments, and the highly acidic lysosome. Drives them into cellular lysosomes.
Some weak base drugs accumulate in tissues high in lysosomes, including lungs, liver, muscle, and brain.
A weak acid, such as ibuprogen, tends to become charged at _______ pH
A weak acid, such as ibuprogen, tends to become charged at HIGHER pH
A weak base tends to become charged at ______ pH
A weak base tends to become charged at LOWER pH
For a weak acid drug, the majority will be readily absorbable at pHs _______ its pKa
For a weak acid drug, the majority will be readily absorbable at pHs BELOW its pKa
For a weak base drug, the majority will be absorbable at pHs _______ its pKa
For a weak base drug, the majority will be absorbable at pHs ABOVE its pKa
CYP2D6 polymorphism
20-25% of drugs (esp. B-blockers, anti-arrhythmics, anti-depressants, anti-psychotics). 75 variants. Most decrease activity, one increases it. (autosomal recessive).
e.g. CYP2D6 inactivates metoprolol
CYP2C9 Polymorphism:
CYP2C9 - 15% of drugs e.g. anti-epileptics, anti-coagulants, ACE inhibitors, NSAIDs. 3 variants (all decrease activity. Autosomal recessive.
e.g. inactivates warfarin normally - so decreased activity of CYP2C9 results in drug toxicity
CYP2C19 Polymorphism:
CYP2C19 - 5% of drugs (e.g. PPIs, BZs, B-blockers, anti-depressants).
All decrease activity. Autosomal recessive.
e.g. Omeprazole is normally inactivated by CYP2C19, so a decrease in CYP activity results in excess drug.
__________ participates in the absorption/clearance of numerous drugs
p-Glycoprotein participates in the absorption/clearance of numerous drugs
