Pharmacokinetics Flashcards
Name four relevant drug reservoirs.
- Stomach
- Albumin
- Tissue (bone, liver, thyroid)
- Fat
How does grapefruit juice affect CYP 450 metabolism?
Inhibits CYP3A4, increasing bioavailability of many orally administered drugs
What is pharmacogenomics?
- Application of genomic information towards the discovery and devo of novel specific drugs
- Such drugs may targeted for selective use among specific patient populations
NOTE: pharmacogenomics/genetics also aim to clarify the underlying basis for idiosyncratic drug responses -> physicians will be increasingly responsible for managing appropriate therapeutic strategies by tailoring drug dosage regimens correlating to patient’s genetic profile
What is the one compartment open pharmacokinetic model (single IV dose)?
- Assumes the entire human body is one compartment.
- Works for drugs distributed fairly uniformly throughout the body.
- Assumes an open system (excretion)
- An adequate representation for many, but not all, drugs
What is the minimum effective concentration?
No responses will be observed below this concentration.
Define absorption.
Describes the rate at which a drug leaves its site of administration and the extent to which that occurs
Briefly describe carrier-mediated transport.
- Some drugs are too large and/or too polar to diffuse across lipid membrane. These molecules enter cells via carrier that facilitates their mvmt down concentration gradient across membrane
- This transport cycle is a reversible process dictated by electrochemical gradients and concentrations of substrates and any co- or counter-transported ions
What is P-glycoprotein (MDR1)?
An efflux pump that limits the utility of chemotherapeutic agents
How does gender impact CYP 450 metabolism?
- There are certain CYP 450 enzymes known to be stimulated by androgens, and are therefore of higher abundance in males
- There are also certain CYP 450 enzymes known to be under control of estrogen, and are thus in higher abundance in females
What is systemic clearance?
- The sum total of clearance by the various organs
- CL = CL(renal) + CL(hepatic) + CL(other)
What is a half-life (T1/2)?
The time it takes for the plasma concentration or amount of drug in the body to be reduced by 50%
Can a slight change in the binding of highly bound drugs can result in significant changes in clinical response or cause a toxic response? Why or why not?
- Yes.
- Because it is the free drug in plasma that equilibrates with the site of pharmacologic or toxic response, i.e., a change from 99% bound to 98% bound can result in almost a 100% change in free concentration, which can cause a significant alteration in response
NOTE: Greatest concern for drugs w/narrow therapeutic window and when dosing regimens or elimination is altered
What are the 5 properties of biotransformation (enzymatic) reactions?
- Obey Michaelis-Menton kinetics:
- > V = V(max) [S] / (Km + [S])
- > S = substrate concentration, Km = Michaelis constant - Rxn rate is proportional to level of enzyme at saturating substrate concentrations
- Rxn rate is proportional to substrate when substrate is limiting
- Max rate achieved when enzyme saturated
- They may competitively or noncompetitively inhibited by other substrates
What are the two phases of drug biotransformation reactions?
- Phase I: functionalization
- Phase II: biosynthetic (or conjugation)
Which will provide tighter control of drug administration, increasing the dose, or decreasing the dose intervals?
- You will have tighter control if you shorten the dose intervals than if you increase the dose amount
- The more dose you give, the bigger the fluctuations
- In the same way, a longer interval will lead to more decay time, and more fluctuation
What is zero order kinetics?
- If the enzymes that metabolize the drug are rate-limiting, i.e., the enzyme is saturated at usual levels of drug in the body, then the same amount of drug (ug/hr) metabolized regardless of level of drug
- No plateau is observed
- EX: ethanol, heparin, phenytoin, aspirin, amobarbital, tetracycline
NOTE: same LD equation applies, LD = (Vd x Css)/F; Km is dose producing 50% of max elimination rate; Vm is max rate of the process
Describe sublingual drug administration, including its advantages and disadvantages.
Formulated in rapidly dissolving tablet, and may be placed under tongue where rich blood supply promotes rapid absorption
- Advantages:
1. First pass (portal vein) bypassed, so > bioavailability (ex: Nitroglycerin)
2. Rapid absorption b/c good blood supply in mouth
3. Drug stability -> mouth pH relatively neutral - Disadvantages:
1. Holding dose in mouth inconvenient
2. Useful when drug dosage is small
What are the four processes that govern the onset, intensity, and duration of drug action?
- Absorption 2. Distribution (only “free” drug accessible to tissues and locus of action) 3. Metabolism 4. Excretion (metabolism + excretion = elimination)
Why is the volume of distribution important?
If a drug distributes throughout total body water (around 40L), its concentration in all of these areas will be different than if it distributes only to the vasculature -> critical for dosing
What are microsomal enzymes?
Drug metabolizing enzymes associated with ER fragments called microvesicles, or microsomes (following homogenization and centrifugation)
What is the volume of distribution (Vd)?
- The fluid volume that would be required to contain all of the drug dose at the same concentration as exists in the blood or plasma
- V(d) = amount of drug in the body/C, where C = blood concentration
- For some drugs, the V(d) describes the primary fluid compartments in which a drug is distributed. For others, the V(d) has no relationship
1. EX: Imipramine has an apparent V(d) of 1,000 L, so the drug must concentrate in some organ or tissue because as it does so, its concentration in blood becomes increasingly small, making V(d) increasingly large
Describe percutaneous drug admin. What are some examples of patches?
- Creams or ointments applied to skin for local effect
- Also may be useful in patches for drugs that are highly lipid soluble and can pass through epidermis
- Examples of patches include: fentanyl (narcotic), nicotine, nitroglycerine, hormone (birth control) patches
How do drugs themselves affect drug metabolism?
- Large # of drugs can cause an increase over time in liver enzyme activity -> can increase metabolic rate in same or other drugs
- Onset 3-12 hours, maximal 1-5 days, persistence 5-12 cays
- Chronic administration can lead to a situation where there is a viscious cycle of dose escalation -> accumulation of toxic metabolites can also occur
- Broad: induce metabolism of themselves and a number of other drugs (ex: phenobarbitol)
- Narrow: induce metabolism of themselves and smaller # (narrower spectrum) of other drugs (ex: 3-MC)
NOTE: induction is generally a reversible process
Drug A has a 20% bioavailability and Drug B has 80% bioavailability. If 400mg of Drug A is given every 6 hours, how much of Drug B would you give in this same time interval?
- 100mg because Drug B has a higher bioavailability
- If the bioavailability were lower, you would have to give more of the drug to get to the same steady state
What are two major factors controlling transcapillary mvmt of drugs?
- Lipid solubility
- Molecular size
How are volume of distribution and the idea of drug reservoirs related?
Example: if 50% of drug accumulated in thumb, only the other 50% would distribute to the tissue(s) you are targeting -> this will TAKE AWAY drug that would normally be expected to distribute to other tissues, and alter the time course of the drug, maintaining a long descending phase of drug concentration (i.e., if drug later redistributes to the desired tissue)
How do intestinal motility and transit time affect drug absorption from the GI tract?
Contractions of small intestine regulate time the food is in contact with reabsorptive epithelium -> faster contraction = faster transit time
What are genotypic polymorphisms?
- Differences in DNA sequences encoding specific proteins
- Can be readily observed by molecular bio techniques like PCR and RFLP
- Can be mediated by changes as small as SNP’s
- Unless screened, these differences can remain silent until individual is “challenged” by a drug -> resulting response is characteristic of the person’s phenotype
What is the equilibrium and Henderson-Hasselbach equation for acids and bases?
- Acids
- HA A- + H+
- pH = pKa + log(A-/HA)
- Bases
- BH+ B + H+
- pH = pKa + log(B/BH+)
Briefly describe intraarterial drug administration.
- Can be used for delivery to specific target organs
- Requires great care, and is reserved for experts
What is TPMT?
- Thiopurine methyltransferase enzyme
- Handles a small fraction of Phase II drugs, but is very important in metabolizing many DNA-modifying drugs used in anti-cancer therapy
Name 3 reasons to study pharmacokinetics.
- There is a relationship b/t the concentration of a drug (from its accessible compartment) and its effects
- Develop a rational framework for dosing
- Improve therapeutic effects by selecting dosing regimens to match patient parameters
Why do many drugs accumulate in tissues at higher concentration than those found in EC fluids and blood? Provide an example.
- Often arises from active transport or binding -> tissue binding typically arises through interactions with proteins and/or phospholipids (EC or IC)
- Binding to cellular constituents is usually saturable and reversible -> dependent on concentration, affinity, and binding capacity of tissue and physicochemical properties of the drug
How do you calculate the clearance for a particular organ?
- CL = Q [(Ca - Cv)/Ca] = Q x E
1. Q = blood flow to the organ
2. E = extraction ratio
3. Ca = arterial drug conc; Cv = venous drug conc - For a drug cleared by a particular organ, clearance by that organ is most critical (DUH!)
- Blood flow (i.e., presentation of the drug) to the organ is the limiting variable
How does the blood perfusion rate affect drug distribution? Where is this rate the highest?
- Greater blood perfusion rate = greater drug distribution to an organ
- Total blood flow greatest to: brain, kidneys, liver, and muscle
- Highest perfusion rates to: brain, kidneys, liver, and heart -> expected that total drug concentration would rise most rapidly in these organs
How is the thyroid a drug reservoir?
Concentrates iodine
Does the time point at which drugs enter their therapeutic window vary by route of administration?
Yes. Oral drugs take longer to have an effect (vs. IV) because they must reach the minimum effective concentration at their sites of action.
What are the 5 mechanisms of metabolic inhibition?
- Competition among substrates for enzyme (ex: cimetidine)
- Inactivation by formation of tight complex with the heme (ex: cobalt)
- Depletion of cofactors; generally more commone with Phase II (ex: GSH depletion due to oxidative stress)
- Enzyme inhibitors (ex: MAOI)
- Increased degradation of enzyme (ex: CCl4)
What two processes determine the duration of drug action and control the rate of termination?
Elimination by the processes of metabolism and excretion
Why are some drugs administered directly to the cornea?
For local effect
Which CYP enzymes encode the enzymes involved in the majority of biotransformations?
CYP1, CYP2, and CYP 3
What happens when structural changes occur in proteins important for a drug’s effect?
Differences between individuals will be expected in responses to this drug -> genetic polymorphism may dictate changes in structure and amount of protein
What is hydrolysis in Phase I rxns?
- Addition of water with breakdown of molecule
- Performed in blood plasma or and liver by esterases
- Esters (R-O-C=O-CH3) -> Alcohol and acid (ROH + CH3-COOH)
Provide an example of drug “redistibution.”
- Thiopental: rapid acting anesthetic delivered to brain
following IV admin b/c a highly perfused tissue - But, distribution to brain not exclusive, and plasma
concentration falls rapidly as it is delivered to other tissues -> concentration in the brain will mirror that in the plasma and fall, as well, thus terminating its action - In contrast, fat tissue will gradually accumulate the drug because of its high lipid solubility
What are the two mechanisms of biotransport?
- Passive diffusion 2. Carrier-mediated biotransport: A) Facilitated diffusion, and B) Active transport
What factors determine if a drug is uptaken by pinocytosis?
- Often depends on if there is a carrier mechanism
- Very large drugs may be too big for facilitated transport b/c you can’t have too large of a hole in the cell
- Tends to be slower, but all carrier processes are limited by their turnover rate
How is the stomach a drug reservoir?
Traps basic drugs due to ionization (ex: codeine)
What is Cinetidine?
- An acid-reflux reducer that is an inhibitor of multiple classes of CYP 450
- Will lead to decrease in other drug elimination, and increase in their plasma concentrations
NOTE: It is important to understand what drugs a patient is taking concurrently
What is phenotypic variation in pharmacogenomics? How does it vary in a monogenic vs. polygenic trait?
- Response to a drug for which a pt has a polymorphic enzymatic process
- Can be characterized by frequency distribution patterns, and be indicative of number and extent of genotypic differences
- Monogenic trait: 2 or 3 distinct population distributions
- Polygenic trait: only 1 population distribution
What is oxidation in Phase I rxns?
- Addition of oxygen and/or removal of H -> most oxidation steps occur in ER
- Common examples include:
1. Alkyl group (CH3-CH3) to an alcohol (CH2OH-CH3)
2. Aromatic ring to phenol (hydroxyl on ring)
3. Oxidation at S or N to generate sulfoxide, or nitroxide derivative
NOTE: Multiple modifications may occur at different sites within the parent compound
How do most drugs cross biological membranes?
Passive diffusion
Describe absorption, metabolism, and excretion in the rising phase vs. the falling phase.
- Rising phase: Abs > Met + Exc - Falling phase: Abs < Met + Exc
What are the two primary ways in which a drug’s effect “terminate?”
- Usually occurs by metabolism and excretion
- May also occur by redistribution from site of action to other tissues or to bound proteins -> one reason for this is blood flow differences b/t tissues or organs that see the drug initially
What is the therapeutic index?
- Therapeutic index = MTC/MEC - MTC = minimum toxic concentration - MEC = minimum effective concentration - Drugs with HIGH therapeutic index are relatively safe
Where in the cell do most biotransformation reactions take place? Are these locations different for Phase I and Phase II reactions?
- Most drug metabolizing enzymes are found in the ER and cytosol, but additional activity is found in mitochondria, nuclear envelope, and PM
- Phase I: most take place in ER
- Phase II: enzymes primarily localized in cytosol
What is the major catalyst of Phase I drug biotransformation?
CYP 450 monooxygenase enzyme family
What is a loading dose? When do you use it? How do you calculate it?
- Desired steady state of a drug times the volume of distribution adjusted for bioavailability
- Used in situations when you can’t wait 5 half-lives to achieve therapeutic range (i.e., heart attacks, seriuous heart failure, overwhelming bacterial infections, etc.)
- LD = (Css x Vd)/ F
- Can be esp. dangerous due to high concentrations achieved -> followed-up with maintenance dose to keep Css in desired therapeutic window:
1. Dosing rate = (target Css x CL)/F
What is clearance?
- The theoretical volume of fluid (i.e. blood, or plasma) from which a drug is removed per unit time
- CL = rate of elimination/concentration
Does the decline of drug concentration vary by route of administration?
No. decline of drug concentration over time follows a characteristic time course, regardless of route of administration.
What is the most important concept to consider when designing a rational regimen for long-term drug administration?
- Clearance
- Clinicians usually want a steady-state concentration of drug within the therapeutic window -> to achieve this, they must administer the drug at the same rate it is eliminated: dosing rate = CL x Css
- When administered at this rate, the drug will eventually reach a plateau
What are the differences and similarities between facilitated diffusion and active transport? Provide an example of each.
- Facilitated diffusion: mvmt with the concentration gradient and *without *energy; exhibits saturation
- Example: Riboflavin, Vit. B12
- Active transport: mvmt *against *the concentration gradient *with *energy use; exhibits saturation
- Example: 5-fluorouracil
Describe the cytochrome P450 enzyme complex.
- Drug binds to oxidized form of P450 enzyme, forming a complex
- Reduced through P450 reductase (which is oxidized) to make reduced form of enzyme combined with drug
- Molecular O2 added, oxidizing drug, eliminating H2O, and releasing oxidized P450 to begin a new cycle
- Meanwhile, P450 reductase, which was oxidized while reducing P450 enzyme, is restored to reduced form via NADPH (and also ready for the next cycle)
NOTE: one O added to drug, and the other reduced to form H2O; NO ATP required
Describe the solubility requirements for a drug to get INTO and OUT OF a membrane.
Must be soluble in the lipid material of the membrane to cross the membrane barrier, and has to be soluble in the aqeous phase to get out of the membrane