Kinetics and Dynamics Flashcards
How do large molecule drug therapies compare to small molecule ones?
- large molecules are produced by recombinant engineering
- they are more targeted therapies
- they are only given parenterally, and their slow absorption leads to multi-compartment kinetics
- mabs in particular have long elimination half-life because their Fc regions bind protective receptors
How is bioavailability defined mathematically?
F = (Oral AUC)/(IV AUC)
What does AUC represent?
the total amount of drug available over time (total drug exposure)
For two drugs to be considered bio equivalent, what must be true?
they must have equivalent Cmax, Tmax, and AUC
How is volume of distribution calculated? What does it represent?
Vd = (amount of drug IV) / (initial plasma concentration)
- it represents the relative distribution between plasma and the rest of the body
How is volume of distribution interpreted?
- Vd = 0.045 L/kg = plasma
- Vd = 0.20 L/kg = ECF
- Vd = 0.60 L/kg = TBW
- Vd > 0.70 L/kg = tissue distribution
What sorts of drugs tend to have a Vd in plasma, ECF, TBW, and tissue?
- plasma: plasma-protein bound drugs and very large drugs
- ECF: large, water-soluble drugs
- TBW: small, water-soluble drugs
- tissue: drugs that avidly bind tissue
List five factors that affect drug distribution?
- blood flow to the organ
- solubility of the drug
- level of binding to substances in the blood
- transporters
- ion-trapping
Which enzyme metabolizes most drugs?
CYP3A4 metabolizes 50-60% of current drugs
What is the “first pass effect”?
- the idea that an orally administered drug is absorbed via the gut and immediately carried to the liver where it is subjected to enzymatic metabolism before every entering the systemic circulation, limiting the available amount
- largely mediated by CYP3A4 expressed in the GI tract and by hepatocytes
Acetaminophen is metabolized by what enzyme?
CYP2E1
Warfarin is metabolized by which enzyme?
CYP2C9
List the key inducers of CYP.
- anticonvulsants (phenobarbital, primidone, phenytoin, carbamazepine)
- rifampin
- polycyclic chemicals
- glucocorticoid drugs
- chronic alcohol
- St. John’s wort
List the key inhibitors of CYP.
- cimetidine
- erythromycin
- ketoconazole
- chloramphenicol
- disulfiram
- acute alcohol
- grapefruit juice
List five drugs for which the FDA recommends pharmacogenomic testing before prescribing.
- warfarin
- isoniazid
- mercaptopurine
- irinotecan
- codeine
List the three kinds of phase 1 drug metabolism reactions.
- oxidation
- reduction
- hydrolysis
List the six kinds of phase 2 drug metabolism reactions. What is the effect of each?
- glucuronidation (increase water solubility)
- sulfate conjugation (increase water solubility)
- glycine conjugation (increase water solubility)
- acetylation (increase lipid solubility)
- methylation (increase lipid solubility)
- glutathione conjugation (detoxification)
Renal secretion of anions are blocked by what drug?
probenecid
Renal secretion of cations are blocked by what drug?
N-methyl nicotinamide
Describe ion trapping of weak acids.
- a weak acid is ionized when they donate a proton
- therefore, they are trapped in slightly basic environments
Describe ion trapping of weak bases.
- a weak base is ionized when they receive a proton
- therefore, they are trapped in slightly acidic environments
What is the difference between zero order and first order drug kinetics? How do the graphs of these compare? Which is more common?
- those with zero order kinetics are cleared at a constant rate, one that is independent of their concentration
- those with first order kinetics have a pseudo-half life as their clearance depends on their concentration (clearance = -K[C])
- zero order kinetics produce a linear line on an arithmetic scale while first order do so on a log scale
- most drugs experience first order kinetics
After any dosing change, how long will it before a new steady-state is reached?
4-5 half lives
Drug X has a half-life of 8 hours and is eliminated via first-order kinetics. A single dose provides therapeutic levels for 16 hours. Doubling the dose will provide a therapeutic level for how many hours?
- 24 hours
- doubling the dose offers one additional half life before the drug falls below therapeutic levels
What fraction of a steady state dose is reached after 1, 2, 3, 4, and 5 half lives of dosing?
- after one half life, it accumulates to 50% steady state
- after two, 75 percent
- after three, 87.5 percent
- and so on
Which pharmacokinetic properties predict the longest half-life?
- high volume of distribution and low clearance will have the longest-half life
- as a result, the largest value for Vd/CL will have the longest half-life
Most absorption occurs via what process?
passive diffusion
List four seven factors that affect drug absorption.
- solubility
- dissolution
- concentration
- blood flow
- absorbing surface
- pH
- contact time
How is the ratio of ionized-to-unionized drug calculated?
ratio = 10^(pKa - pH) with the ionized form predominating when pH > pKa for acids and when pH
Drug secretion via what mechanism is subject to drug-drug interactions?
any that is mediated by a carrier or transporter
How does facilitated diffusion differ from active transport?
- facilitated diffusion does not require energy and moves a substance down it’s concentration gradient
- active transport utilizes energy equivalents to move a substance against it’s concentration gradient
Which drugs are absorbed via pinocytosis?
exceptionally large chemicals and drugs (proteins and complexes)
What mechanisms reduce the bioavailability of orally administered drugs?
- absorption dependent on gastric emptying time
- destruction of drug by enzymes and pH
- drugs bind or complex with GI contents
- subject to first-pass effects
What four drugs are known for being subject to high first-pass effects?
- morphine
- nitroglycerine
- lidocaine
- HIV protease inhibitors
What is a depot preparation of a drug?
one in oil that is administered intramuscularly and forms a slowly absorbed reservoir of drug
Which experiences slower drug absorption, intramuscular or subcutaneous injection? Why?
subcutaneous is slower because blood flow is more limited than intramuscular
What are the benefits or situations in which rectal administration of a drug would be preferred?
- useful when oral ingestion is precluded by vomiting or an unconscious state
- does not pass through liver, and therefore isn’t subject to the first pass effect
Name four anatomical fluids subject to drug exclusion.
- CSF
- ocular fluid
- pleural fluid
- lymph fluid
What are the two main plasma proteins to which drugs bind? How are these affected by inflammatory states? How does this affect drug distribution?
- albumin is down regulated in inflammatory states, increasing the distribution of drugs it binds
- a1-acid-glycoprotein is unregulated, decreasing distribution of the drugs it binds
When during gestation, is the fetus most susceptible to teratogenic effects?
the first trimester
Which drugs are most likely to pass the placental barrier?
those that are very lipid soluble
Drugs with one of which three properties are likely to accumulate in breast milk?
- weak bases (ion-trapping)
- tetracyclines (chelate calcium)
- lipid-soluble drugs (fat content of milk)
How are drugs with nitro groups reduced in our bodies?
primarily by gut bacteria
Describe the mechanism of acetaminophen toxicity.
- acetaminophen is normally metabolized by sulfating and glucuronidation
- when high levels are present, it is metabolized to a toxic intermediate by CYP2E1
- in an otherwise normal individual, the toxic intermediate is neutralized by glutathione
- chronic alcohol, however, up-regulates CYP2E1 while also depleting glutathione stores, leaving more toxic metabolites
Liver metabolism in the elderly is often declined. Is phase I or II more affected?
phase I are more likely diminished while phase II reactions are more likely to be preserved
Drugs of what size are completely filtered when passing through the nephron?
MW < 5000
Drugs that aren’t protein bound, aren’t reabsorbed, and have a MW < 5000, are excreted at what rate?
125 mL/min (approximately GFR)
Drugs that are eliminated via tubular secretion and aren’t reabsorbed, are excreted at what rate?
660 mL/min (approximately RPF)
Name two agents that bind drugs in the intestine, preventing their absorption and enhancing their excretion.
- charcoal
- cholestyramine
What is the enterohepatic cycle?
a cycle whereby drugs undergo hepatic (biliary) secretion but are reabsorbed in the GI tract and re-enter circulation, thus extending their half-life
Which compounds are typically excreted via biliary secretion?
glucuronide conjugates greater than 350 MW
Give three examples of substances which experience zero-order kinetics.
- ethanol
- phenytoin at high doses
- salicylate (e.g. aspirin) at high doses
How is drug clearance defined?
the volume of plasma that is irreversibly cleared of drug per unit time
How is renal clearance calculated?
CL® = (urine concentration)(rate of urine flow)/(plasma concentration)
What are one-compartment and multi-compartment drugs?
- one-compartment are those that experience rapid distribution, thus whatever happens in plasma happens in all other tissues (parallel lines)
- multi-compartment are those that are slowly distributed, thus changes in drug concentration vary from compartment to compartment
What is a loading dose?
a very large dose that gets you to the desired steady state immediately, which is then followed by maintenance doses
Define agonist, inverse against, and antagonist.
- agonist: a drug that increases the activity of its receptor upon binding
- inverse agonist: a drug that reduces the activity of its receptor upon binding
- antagonist: a drug that that interferes with the ability of an agonist to bind its receptor (if it binds the receptor, it simply blocks binding of another substance, it doesn’t change receptor activity)
Define competitive and noncompetitive antagonist.
- competitive: reversibly binds the receptor active site, blocking binding of the agonist (looks like less ligand)
- noncompetitive: blocks agonist binding by irreversibly binding the active site or binding outside the active site on the receptor (looks like fewer receptors)
What is the difference between a graded and a quantal dose-response curve?
- graded: a graph of increasing response of an individual to increasing dose
- quantal: a graph of the fraction of a population that shows a specific response at progressively increasing doses
What is the difference between potency and efficacy?
- potency: ability to bind the receptor
- efficacy: ability to activate the receptor
What is receptor sparing? How can you identify instance in which it exists?
- identifiable by a mismatch between Kd and EC50
- effects occur at lower concentrations of ligand than binding parameters predict (i.e. not all receptors have to be occupied for maximal effect)
- occurs when receptor activation is not the limiting step in the signal transduction pathway
How do spare receptors affect application of a non-competitive antagonist or competitive?
- higher doses of non-competitive antagonist are required before effects are seen because maximal effect can be achieved even when fewer receptors are available for agonist binding
- spare receptors do not influence the response of a competitive inhibitor
Describe the AC signaling cascade.
- AC is activated (usually by a Gas protein)
- this drives increased cAMP production
- cAMP activates PKA, which has downstream effects
List eight ligands that function to activate Gs and the AC signal cascade.
- ACTH
- TSH
- FSH
- B agonists
- D1-like receptor agonists
- glucagon
- PGE2
- PGI2
List five ligands that function to activate Gi and inhibit the AC signal cascade.
- a2 agonists
- M2 agonists
- D2-like receptor agonists
- serotonin agonists
- opioid mu agonists
Describe the polyphosphoinositide signaling cascade.
- an agonist activates Gq, which activates PLC
- PLC cleaves PIP2, yielding IP3 and DAG
- DAG activates PKC
- IP3 releases intracellular calcium
List five receptors that function via the polphosphoinositide signaling cascade to induce vasoconstriction.
- a1-adrenoreceptors
- vasopressin
- thromboxane A2
- angiotensin receptors
- endothelin receptors
List three receptors that function via the polphosphoinositide signaling cascade to induce vasodilation.
- muscarinic receptors
- histamine
- bradykinin
Describe EDRF synthesis and signaling cascade. Activation of what four receptors will induce this process?
- acetylcholine, histamine, bradykinin, and VEGF induce NOS expression
- NOS converts arginine to citrulline and NO
- NO activates GC by binding the heme iron in the enzyme
- GC then increases cGMP production
- cGMP activates PKG, which activates myosin
- thereby inducing vasorelaxation
List six ligands that signal via nuclear receptors.
- glucocorticoids
- mineralcorticoids
- sex steroid hormones
- vitamin D
- thyroid hormone
- retinoic acid
Nuclear receptors typically have what three domains?
- ligand binding
- DNA binding
- transcription-activating domain
List the common signal coupling mechanism in order of fastest to slowest onset.
- ligand-gated ion channels (msec)
- GPCRs (seconds)
- membrane bound enzymes (TKR) and cytoplasmic receptors (min)
- nuclear receptors (hours)
What is the therapeutic index? How is it calculated?
- an index for drug safety
- TI = LD50/ED50
What is the margin of safety? How is it calculated?
- an index for drug safety
- MS = LD1/ED99
What is pharmacokinetic tolerance? What is pharmacodynamic tolerance?
- kinetic: a diminished drug response due to the induction of drug metabolizing enzymes
- dynamic: a diminished drug response due to changes in receptor number or function
List five drugs associated with type I hypersensitivities.
- B-lactam antibacterials
- neuromuscular blockers (quaternary ammonium compounds)
- quinolones
- platinum-based cytotoxic drugs
- foreign proteins
List four classic drug idiosyncrasies.
- abnormal serum cholinesterase: develop apnea when given succinylcholine
- slow acetylators: isoniazid-induced VitB6 deficiency, producing sideroblastic anemia or neuropathy)
- G6PDH deficiency: hemolytic anemia following primaquine, sulfonamides, or nitrofurantoin
- barbiturate-induced porphyria in those with abnormal heme synthesis
List three drugs known for displacing other drugs from plasma proteins.
- oral hypoglycemic agents
- oral anticoagulants
- antimetabolites
